Use of tricyclic derivatives of 1,4-dihydro-1,4-dioxo-1H-naphthalene, novel compounds obtained and their application in theraphy

ABSTRACT

The invention concerns the therapeutic use of tricyclic salts and their pharmaceutically acceptable salts having the general formula:                    
     in which: 
     A is either a sulfur atom, an oxygen atom, or an R 3 N radical where R 3  is a hydrogen atom, a C 1 -C 5  alkyl radical, or a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heteroaromatic ring. 
     R 1  is either a C 1 -C 5  alkyl radical, 
     or an R 4 NH radical where R 4  is a hydrogen atom, a C 1 -C 5  alkyl radical, or a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heteroaromatic ring, 
     or an aromatic ring that may or may not be substituted by one or more acceptor or donor groups, or a heteroaromatic ring having one or more heteroatoms, which may or may not be substituted by acceptor or donor groups. 
     R 2  is a hydrogen atom, halogen atom, a C 1 -C 5  alkyl radical, an oxygen atom that may or may not be substituted by a C 1 -C 5  alkyl radical, or an NR 5 R 5 , radical where R 5  and R 5 , are, independently of each other, a hydrogen atom, an oxygen atom or monovalent C 1 -C 5  organic radicals.

The present invention concerns the use of tricyclic derivatives and theuse of their pharmaceutically acceptable salts for the preparation of adrug intended for the treatment of diseases connected with an alterationof venous and/or inflammatory edema, and concerns the novel compoundsobtained. It refers more particularly to the tricyclic derivatives of1,4-dihydro-1,4-dioxo-1H-naphthalene. The invention concerns thetherapeutic application of all these compounds.

The synthesis of 1H-naphtho[2,3-d]imidazole-4,9-diones, substituted inposition 2, is described in J. Heterocyl. Chem., 6(6), 909-916, 1969, byE. I. Carroll, and J. T. Blackwell. in addition, the document Zh. Org.Khim, 3(1), 162-168, 1967, by G. A. Efimova, and L. S. Efros, concernsthe preparation of 1,2-dimethyl-1H-naphth[2,3-d]imidazole-4,9-dione.Finally, the document J. Am. Chem. Soc., 76, 4148-4152, 1954, by J. R.E. Hoover, and A. R. Day, shows the preparation of derivatives of1H-naphthoimidazole-4,9-dione from2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene.

The article in J. Prakt. Chem., 319(2), 254-258, 1977 by Ahmed S. Hammamand Osman Abdel-Magid describes the synthesis of2-amido-3-chloro-1,4-dihydro-1,4-dioxonaphthalene from2,3-dichloro-1,4-dihydro-1,4-dioxonaphthalene, a compound that can beused as an intermediate for the subsequent synthesis ofnaphtho[2,3-d]oxazole-4,9-diones, which may or may not be substituted atposition 2. U.S. Pat. No. 3,039,925, of Jun, 19, 1962 and a Germanpatent application of Apr. 24, 1967 by Gerhard Domagk, Karl W.Schellhammer, Siegfried Peterson, and Hans B. Koenig concern thesynthesis of 2-methylnaphtho[2,3-d]oxazole-4,9-dione carried out by K.Fries and P. Ochwat (Berichte, 56, 1926 (1923)).

Japanese Patent 61,251,675 by S. Hiroyuki, as well as the article inCollect. Czech. Chem. Commun., 50(1), 71-79, 1985 by A. S. Hammam, andB. E. Bayoumy and in the document J. Heterocyclic Chem., 25, 901-906,1988 by A. R. Katritzky and W. Q. Fan, describe the preparation of thenaptho[2,3-d]thiazole-4,9-diones.

The tricyclic derivatives and their pharmaceutically acceptable saltsaccording to the present invention have the general formula:

in which:

A is either a sulfur atom, an oxygen atom, or an R₃N radical where R₃ isa hydrogen atom, a C₁-C₅ alkyl radical, or a substituted orunsubstituted aromatic ring, or a substituted or unsubstitutedheteroaromatic ring.

R₁ is either a C₁-C₅ alkyl radical,

or an R₄NH radical where R₄ is a hydrogen atom, a C₁-C₅ alkyl radical,or a substituted or unsubstituted aromatic ring, or a substituted orunsubstituted heteroaromatic ring,

or an aromatic ring that may or may not be substituted by one or moreacceptor or donor groups, or a heteroaromatic ring having one or moreheteroatoms, which may or may not be substituted by acceptor or donorgroups.

R₂ is a hydrogen atom, halogen atom, a C₁-C₅ alkyl radical, an oxygenatom that may or may not be substituted by a C₁-C₅ alkyl radical, or anNR₅R₅ radical where R₅ and R_(5′) are, independently of each other, ahydrogen atom, an oxygen atom, or monovalent C₁-C₅ organic radicals.

In the invention the term “acceptor or donor groups” is defined as aC₁-C₅ alkyl radical, a halogen atom, or an oxygen atom, which may or maynot be substituted by a C₁-C₅ alkyl radical, or an NR₆R_(6′) where R₆and R_(6′) are, independently of each other, a hydrogen atom, an oxygenatom, or monovalent C₁-C₅ organic radicals.

The invention also concerns the following novel products:

4,9-dihydro-4,9-dioxo-1,2-dimethyl-1H-naphtho[2,3-d]imidazole sulfate,

4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)-1H-naphtho[2,3-d]imidazole,

4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)-naphtho[2,3-d]oxazole,

4,9-dihydro-4,9-dioxo-2-(3-fluorophenyl)naphtho[2,3-d]oxazole,

4,9-dihydro-4,9-dioxo-2-(4-fluorophenyl) naphtho[2,3-d]oxazole,

4,9-dihydro-4,9-dioxo-2-(2-methylphenyl) naphtho[2,3-d]oxazole,

4,9-dihydro-4,9-dioxo-2-(3-methylphenyl) naphtho[2,3-d]oxazole,

4,9-dihydro-4,9-dioxo-2-(4-methylphenyl) naphtho[2,3-d]oxazole,

2-(2-chlorophenyl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]oxazole,

2-(4-chlorophenyl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]oxazole,

4,9-dihydro-4,9-dioxo-2-(2-thienyl)-naphtho[2,3-d]oxazole,

4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(3-fluorophenyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(4-fluorophenyl)naphtho[2,3-d]thiazole,

2-(2,4-difluorophenyl)-4,9-dihydro-4,9-dioxonaphtho [2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(3-pyridyl)-naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(4-pyridyl)-naphtho[2,3-d]thiazole sulfate,

4,9-dihydro-4,9-dioxo-2-(3-furyl)naphtho[2,3-d]thiazole,

2-(5-chlorofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(2-thienyl)-naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(3-thienyl)-naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-phenylamino-naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-8-methoxy-2-phenylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-5-methoxy-2-phenylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-7-methoxy-2-phenylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-6-methoxy-2-phenylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-8-hydroxy-2-phenylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(1-pyrrolyl)-naphtho[2,3-d]thiazole,

2-(5-bromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho [2,3-d]thiazole,

2-(4,5-dibromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,

2-(3-bromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,

2-(3-bromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,

2-(4-bromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(5-nitrofuran-2-yl)naphtho[2,3-d]thiazole,

2-(5-aminofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,

2-(5-acetamidofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(5-hydroxymethylfuran-2-yl)naphtho[2,3-d]thiazole,

2-(5-acetoxymethylfuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(5-methyl-2-furyl)naphtho[2,3-d]thiazole,

4,9-dihydro-2-(4,5-dimethyl-2-furyl)-4,9-dioxonaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(5-phenyl-2-oxazolyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(2-thiazolyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-6-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-7-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-6-fluoro-2-phenylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-7-fluoro-2-phenylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-6-fluoro-2-(5-methyl-2-furyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-7-fluoro-2-(5-methyl-2-furyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-fluorophenyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-fluorophenyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-methylphenyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-methylphenyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-5-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-8-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole,

6-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)naphtho[2,3-d]thiazole,

7-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)naphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-methoxynaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-methoxynaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(2-furyl) -5-hydroxynaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-hydroxynaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(2-furyl)-6-methoxynaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-(2-furyl)-7-methoxynaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-furyl-6-methylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-furyl-7-methylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-6-methyl-2-phenylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-7-methyl-2-phenylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-furyl-5-methylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-2-furyl-8-methylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-5-methyl-2-phenylnaphtho[2,3-d]thiazole,

4,9-dihydro-4,9-dioxo-8-methyl-2-phenylnaphtho[2,3-d]thiazole.

The invention also concerns the following intermediate products:

1,4-dihydro-1,4-dioxo-5-methoxynaphthalene,

2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene,

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene,

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene,

2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene,

2-amino-3-bromo-6-fluoro-1,4-dihydro-1,4-dioxonaphthalene,

2-amino-3-bromo-7-fluoro-1,4-dihydro-1,4-dioxonaphthalene,

2,3-dibromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene,

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene,

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-fluoronaphthalene,

2-amino-3-chloro-1,4-dihydro-1,4-dioxo-6-methylnaphthalene,

2-amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene,

2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene,

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene,

2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methylnaphthalene.

The invention also refers to the use of tricyclic derivatives and theirpharmaceutically acceptable salts, having the above general formula (I),for the preparation of a drug intended for:

the treatment of functional and organic venous insufficiency;

the treatment of hemorrhoid pathologies;

the treatment of migraine;

the treatment of dermatological and cardiovascular osteoarticularinflammations;

the treatment of states of shock consisting of a large drop in arterialpressure, more particularly in states of septic shock.

Specifically, the compounds of the present invention have the generalformula (I) illustrated below:

where:

A=—NH, —N—C₆H₅, —N—CH₃, O, S, N

R₂=H, —OCH₃, —OH, —F, Cl, CH₃

The present invention also relates to the salts of the compounds offormula (I) of which salts can be prepared. These salts comprise theaddition salts of mineral salts such as hydrochloric acid, hydrobromicacid, sulfuric acid, phosphoric acid, or nitric acid, and the additionsalts of organic salts such as acetic acid, propionic acid, oxalic acid,citric acid, maleic acid, fumaric acid, succinic acid and tartaric acid.

The invention is illustrated by the following nonlimiting examples.

The examples indicated by a number correspond to novel compounds,whereas the examples indicated by a letter correspond to knowncompounds.

In all the examples, the analyses are carried out as indicated below:

Melting point: The analyses are carried out using an apparatus of the“Kofler bench” type LEICA-REICHERT model WME and they are not corrected.

Thin-layer chromatographies: The thin layer chromatographies are carriedout using silica gel plates with a UV₂₅₄ fluorescence indicator, at athickness of 0.25 mm, of the MACHEREY-NAGEL type (Reference 805 023).The elution solvents are indicated for each compound.

Mass spectra: The mass spectra are determined using a spectrometer ofthe AEI MS-50 type or a spectrometer of the FISONS VG PLATFORM type. Theionization mode is indicated for each example.

NMR spectra: The NMR spectra of ¹H and ¹³C are determined using either aspectrometer of the JEOL type, at 270 MHZ and 68 MHZ, respectively, or aspectrometer of the BRUCKER type, at 400 MHZ and 100 MHZ, respectively.The deuterated solvents used are indicated for each analysis.

Infrared spectra: The infrared spectra are obtained using a spectrometerof the NICOLET 205 FT-IR type. They are determined at 1% (weight/weight)in a dispersion in KBr.

EXAMPLE 1 4,9-Dihydro-4,9-dioxo-1,2-dimethyl-1H-naphtho[2,3-d]imidazolesulfate

To a solution of 2 g (8.84 mmol) of4,9-dihydro-4,9-dioxo-1,2-dimethyl-1H-naphtho[2,3-d]imidazole in 300 mLof a methanol/dichloromethane mixture (2/1) heated at 70° C., 1 mL ofconcentrated sulfuric acid is added. The reaction mixture is stirred at70° C. for 2 h, then concentrated at reduced pressure, and the paleyellow precipitate that appears is filtered and washed withdichloromethane, then with ethyl ether, to produce 2 g of4,9-dihydro-4,9-dioxo-1,2-dimethyl-1H-naphtho[2,3-d]imidazole sulfate,in the form of yellow crystals.

Yield: 70%; Melting point: >260° C.; Rf: 0.50 (CH₂Cl₂/Methanol,97.5/2.5); ¹H-NMR (DMSO d₆): δ (ppm); 8.05 (dd, 2H, H-5, H-8,J_(H5-H6)=J_(H7-H8)=8.85 Hz; J_(H5-H7)=J_(H6-H8)=1.73 Hz); 7.85 (m, 2H,H-6, H-7); 5.44 (s, 1H, NH+); 3.98 (s, 3H, CH₃); 2.53 (s, 3H, CH₃);¹³C-NMR (DMSO, d₆): δ (ppm); 177.22, 175.44 (2C, C-4, C-9); 153.46 (1C,C-2); 138.96 (1C, C-3a); 134.10, 134.01 (2C, C-6, C-7); 132.30, 131.93(3C, C-8a, C-9a, C-4a); 126.24, 126.13 (2C, C-5, C-8); 32.33 (1C, CH₃);12.30 (1C, CH₃); IR (KBr): ν (cm⁻¹); 3414-2400 (broad NH⁺ band); 1674(C═O).

EXAMPLE 24,9-Dihydro-4,9-dioxo-2-(2-fluorophenyl)-1H-naphtho[2,3-d]imidazole

To a suspension of 1.37 g (7.29 mmol) of2,3-diamino-1,4-dihydro-1,4-dioxonaphthalene in 50 mL of water, asolution of 0.77 mL (7.29 mmol) of 2-fluorobenzaldehyde in 5 mL ofglacial acetic acid is added. After 5 h of reflux, the black solidobtained is filtered, then washed three times with 30 mL of water. Thesolid is then redissolved in 2 L of dichloromethane, the organic phaseis washed three times with water, dried over calcium chloride, andevaporated to dryness to produce 1.50 g of chestnut brown crystals. Theproduct is purified on a flash column (support: silica, conditioning:heptane, eluants: dichloromethane/heptane, 95/5, thendichloromethane/methanol, 99/1), resulting in the production—afterevaporation of the solvents at reduced pressure—of 1.00 g of4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)-1H-naphtho[2,3-d]imidazole inthe form of yellow crystals.

Yield: 47%; Melting point: >260° C.; Rf: 0.56 (CH₂Cl₂/ethyl acetate,92/8); MS (I.E.): m/z 292 (M+.); ¹H-NMR (DMSO d₆): δ (ppm); 14.28 (s,1H, NH); 8.12 (m, 2H, H-5, H-8); 8.00 (m, 1H, H-6′); 7.86 (m, 2H, H-6,H-7); 7.60 (m, 1H, H-3′); 7.44 (m, 2H, H-4′, H-5′); ¹³C-NMR (DMSO d₆): d(ppm); 179.13, 175.03 (2C, C-4, C-9); 157.41 (1C, C-2′); 147.88 (1C,C-2); 133.85 (2C, C-6, C-7); 132.67 (3C, C-6′, C-9a, C-3a); 130.62 (2C,C-4a, C-8a); 126.24, 124.82 (3C, C-5, C-8, C-5′); 116.62, 116.31 (2C,C-1′, C-3′); IR (KBr): ν (cm⁻¹); 3339 (NH): 1683, 1665 (C═O).

EXAMPLE 3 4,9-Dihydro-4,9-dioxo-2-(2-fluorophenyl)-naphtho[2,3-d]oxazole

To a solution of 6.0 g (28.8 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 120 mL ofnitrobenzene, 17.10 mL (144.0 mmol) of 2-fluorobenzoic acid chloride areadded with protection from light. After 10 min of stirring at 80° C.,0.20 mL of concentrated sulfuric acid is added. The reaction mixture isheated to reflux for 18 h. After complete cooling, ether is added toproduce a yellow precipitate, which is filtered through fritted glassand washed with ether. This solid is then purified on a flash column(support: silica; conditioning: heptane; eluant:dichloromethane/heptane, 60/40) to produce 2.5 g of4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)-naphtho[2,3-d]oxazole in theform of yellow crystals.

Yield: 30%; Melting point: >260° C.; Rf: 0.60 (CH₂Cl₂); MS (I.E.): m/z293 (M+.); ¹H-NMR (DMSO d₆): δ (ppm); 8.25 (m, 2H, H-5, H-8); 8.19 (m,1H, H-6′); 7.95 (m, 2H, H-6, H-7); 7.76 (m, 1H, H-4′); 7.52 (m, 2H,H-3′, H-5′); ¹³C-NMR (DMSO d₆): δ (ppm); 178.22, 173.06 (2C, C-4, C-9);161.88 (1C, C-2); 158.08 (1C, C-2′); 150.67, 142.83 (2C, C-3a, C-9a);135.37 (1C, C-6′); 134.64 (2C, C-6, C-7); 132.31, 131.94 (2C, C-4a,C-8a); 130.65 (1C, C-4′); 126.79, 126.47 (2C, C-5, C-8); 125.62 (1C,C-5′); 117.32 (1C, C-3′); 113.21 (1C, C-1′); IR (KBr): ν (cm⁻¹); 1693,1680 (C═C).

EXAMPLE 4 4,9-Dihydro-4,9-dioxo-2-(3-fluorophenyl)-naphtho[2,3-d]oxazole

To a solution of 5.00 g (24 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 50 mL ofnitrobenzene, 14.6 mL (120 mmol) of 3-fluorobenzoic acid chloride areadded; after 5 min of stirring, 0.50 mL of concentrated sulfuric acid isthen added with protection from light. After 24 h of reflux and completecooling, 200 mL of ether are added to the reaction mixture. Theprecipitate formed is filtered, then redissolved in 200 mL ofdichloromethane, to which 100 mL of a glacial sodium hydroxide solutionare added. After 6 h of stirring at this temperature, the organic phaseis extracted, washed several times with water and dried over calciumchloride. The solid obtained after evaporation of the solvent ispurified on a medium-pressure column (support: silica; conditioningheptane; eluant: dichloromethane/heptane, 50/50). The yellow crystals soobtained are uncolored and recrystallized in a dichloromethane/heptanemixture (volume/volume) to produce 0.50 g of4,9-dihydro-4,9-dioxo-2-(3-fluorophenyl)-naphtho[2,3-d]oxazole in theform of yellow crystals.

Yield: 7%; Melting point: 230° C.; Rf: 0.50 (CH₂Cl₂/heptane, 95/5); MS(I.E.): m/z 293 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.31 (m, 1H, H-6′); 8.27(m, 2H, H-5, H-8); 8.02 (s, 1H, H-2′); 7.83 (m, 2H, H-6, H-7); 7.63 (m,1H, H-5′); 7.31 (m, 1H, H-4′); ¹³C-NMR (DMSO d₆): δ (ppm); 178, 173 (2C,C-4, C-9); 162.53 (1C, C-3′); 149.37 (1C, C-9a); 143.47 (1C, C-3a);134.85, 134.46 (2C, C-6, C-7); 132.45, 132.08 (2C, C-4a, C-8a); 131.06(1C, C-5′); 127.52, 127.11 (2C, C-5, C-8); 124.74 (1C, C-6′); 117.46,117.15 (2C, C-2′, C-4′); IR (KBr): ν (cm⁻¹); 1695, 1680 (C═O).

EXAMPLE 5 4,9-Dihydro-4,9-dioxo-2-(4-fluorophenyl)-naphtho[2,3-d]oxazole

To a solution of 6.22 g (30 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene in 60 mL ofnitrobenzene, 18.00 mL (150 mmol) of 4-fluorobenzoic acid chloride areadded with protection from light. After 10 min of stirring with reflux,0.20 mL of concentrated sulfuric acid is added. After 12 h and completecooling, ether is added to obtain a yellow precipitate which is filteredthrough fritted glass, washed with ether and purified on a flash column(support: silica; conditioning: heptane; eluant:dichloromethane/heptane, 60/40). The yellow powder obtained afterevaporation of the solvent is uncolored, recrystallized indichloromethane to produce 2.90 g of4,9-dihydro-4,9-dioxo-2-(4-fluorophenyl)-naphtho[2,3-d]oxazole in theform of yellow crystals.

Yield: 33%; Melting point: >260° C.; Rf: 0.60 (CH₂Cl₂/heptane, 80/20);MS (I.E.): m/z 293 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.33 (m, 2H, H-2′,H-6′); 8.28 (m, 2H, H-5, H-8); 7.82 (m, 2H, H-6, H-7); 7.26 (m, 2H,H-3′, H-5′); ¹³C-NMR (CDCl₃): δ (ppm); 166.89 (1C, C-4′); 143.45 (1C,C-3a); 134.42 (2C, C-6, C-7); 132.86 132.55 (2C, C-4a, C-8a); 130.78(2C, C-2′, C-6′); 127.52, 127.07 (2C, C-5, C-8); 121.50 (1C, C-1′);116.82, 116.50 (2C, C-3′, C-5′); IR (KBr): ν (cm⁻¹); 1689, 1669 (C═O).

EXAMPLE 6 4,9-Dihydro-4,9-dioxo-2-(2-methylphenyl)-naphtho[2,3-d]oxazole

To a solution of 5.00 g (24 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 37 mL (280 mmol) of2-methylbenzoic acid chloride, 8 drops of concentrated sulfuric acid areadded with protection from light. After 7 h of reflux and completecooling, the ocher precipitate that forms is filtered through frittedglass, washed with ether, and purified on a flash column (support:silica; conditioning: heptane; eluant: dichloromethane/heptane, 50/50).The yellow powder obtained after evaporation of the solvent isuncolored, and recrystallized in dichloromethane to produce 2.34 g of4,9-dihydro-4,9-dioxo-2-(2-methylphenyl)-naphtho[2,3-d]oxazole in theform of yellow crystals.

Yield: 34%; Melting point: 212° C.; Rf: 0.50 (CH₂Cl₂/heptane, 80/20); MS(I.E.): m/z 289 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.30 (m, 1H, H-6′); 8.27(m, 2H, H-5, H-8); 7.81 (m, 2H, H-6, H-7); 7.47 (m, 1H, H-4′); 7.37 (m,2H, H-3′, H-5′); 2.84 (s, 3H, CH₃); ¹³C-NMR (CDCl₃): δ (ppm); 179.05,173.50 (2C, C-4, C-9); 140.81 (1C, C-2′); 134.77 (2C, C-6, C-7); 133.50(1C, C-3′); 132.50 (1C, C-4′); 130.80 (1C, C-6′); 127.91 127.49 (2C,C-5, C-8); 125.60 (1C, C-5′); 123.45 (1C, C-1′); 22.50 (1C, CH₃); IR(KBr): ν (cm⁻¹); 1668, 1678 (C═O).

EXAMPLE 7 4,9-Dihydro-4,9-dioxo-2-(3-methylphenyl)-naphtho[2,3-d]oxazole

To a solution of 5 g (24 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene in 70 mL of dioxane,one adds, with protection from light, 32.00 mL (240 mmol) of3-methylbenzoic acid chloride; after 5 min of stirring, 0.50 mL ofconcentrated sulfuric acid is added. After 45 min of reflux and completecooling, 200 mL of ether are added, and the precipitate that forms iseliminated by filtration. The red filtrate is evaporated to dryness,redissolved in dichloromethane, washed several times with water, driedand purified on a flash column (support: silica; conditioning: heptane;eluant: dichloromethane/heptane, 50/50). The yellow crystals formedafter evaporation of the solvent are uncolored and recrystallized indichloromethane to produce 3 g of4,9-dihydro-4,9-dioxo-2-(3-methylphenyl)-naphtho[2,3-d]oxazole in theform of yellow crystals.

Yield: 43%; Melting point: 255° C.; Rf: 0.43 (CH₂Cl₂/heptane, 80/20); MS(I.E.): m/z 289 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.26 (m, 2H, H-5, H-8);8.17 (s, 1H, H-2′); 8.13 (m, 1H, H-5′); 7.82 (m, 2H, H-6, H-7); 7.43 (m,2H, H-4′, H-6′); 2.48 (s, 3H, CH₃); ¹³C-NMR (CDCl₃): δ (ppm); 179.13,173.72 (2C, C-4, C-9); 166.95 (1C, C-2); 150.65, 144.17 (2C, C-3a,C-9a); 139.62 (1C, C-3′); 134.81, 134.77; 134.32 (3C, C2′, C-6, C-7);132.86, 132.55 (2C, C-4a, C-8a); 129.54, 129.26 (2C, C-4′, C-5′);127.91, 127.49 (2C, C-5, C-8); 125.86 (1C, C-6′); 125.44 (1C, C-1′);21.71 (1C, CH₃); IR (KBr): ν (cm⁻¹); 1693, 1678 (C═O).

EXAMPLE 84,9-Dihydro-4,9-dioxo-2-(4-methoxyphenyl)-naphtho[2,3-d]oxazole

To a solution of 5.0 g (24 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 80 mL ofdichloromethane, one adds, with protection from light and at ambienttemperature, 16 mL (120 mmol) of 4-methoxybenzoic acid chloride, then0.003 mL of concentrated sulfuric acid. After 3 h of reflux, thereaction mixture is evaporated to dryness; the black oily residueobtained is redissolved in 300 mL of dichloromethane, washed with asolution of 10N sodium hydroxide, then with water, and finally driedover calcium chloride. The product is then purified on a flash column(support: silica 6-35 mm; conditioning: heptane; eluant:dichloromethane/heptane, 60/40), to produce 4.1 g of4,9-dihydro-4,9-dioxo-2-(4-methoxyphenyl)-naphtho[2,3-d]oxazole in theform of yellow-orangish crystals after recrystallization and colorremoval with animal charcoal.

Yield: 56%; Melting point: >260° C.; Rf: 0.44 (CH₂Cl₂/ethanol, 99/1); MS(I.E.): m/z 305 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.28 (dd, 2H, H-5, H-8,J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H5-H7)=J_(H6-H8)=1.73 Hz); 8.24 (d, 2H,H-2′, H-6′, J_(H2′-H3′)=J_(H5′-H6′)=8.60 Hz); 7.80 (m, 2H, H-6, H-7);7.05 (d, 2H, H-3′, H-5′, J_(H2′-H3′)=J_(H5′-H6′)=8.60 Hz); 3.92 (s, 3H,CH₃); IR (KBr): ν (cm⁻¹); 1750, 1680 (C═O).

EXAMPLE 9 2-(2-Chlorophenyl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]oxazole

To a solution of 5 g (24 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 60 mL of dioxane,15.3 mL (120 mmol) of 2-chlorobenzoic acid chloride are added; after 5min of stirring, 0.5 mL of concentrated sulfuric is added. The reactionmixture is heated to reflux for 4 h, and the precipitate obtained afterevaporation of the dioxane at a reduced pressure is dissolved in 200 mLof dichloromethane. To this solution, 100 mL of a cold 10N sodiumhydroxide solution are added. The mixture is stirred for 2 h. Theorganic phase is then extracted, washed several times with water anddried over calcium chloride. The solid residue obtained afterevaporation of the solvent is purified on a medium-pressure column(support: silica; eluant: dichloromethane/heptane, 40/60). The productobtained is recrystallized after color removal in aheptane/dichloromethane mixture (1/1) to produce 5 g of2-(2-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]oxazole in theform of light yellow crystals.

Yield: 67%; Melting point: 216° C.; Rf: 0.42 (CH₂Cl₂/heptane, 80/20); MS(I.E.): m/z 309, 311 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.26 (m, 3H, H-5,H-8, H-6′); 7.82 (m, 2H, H-6, H-7); 7.53 (m, 3H, H-3′, H-4′, H-5′);¹³C-NMR (CDCl₃): δ (ppm); 134.99, 134.87 (3C, C-2′, C-6, C-7); 133.78,132.84, 132.18 (4C, C-3′, C-4′, C-5′, C-6′); 132.38, 132.04 (2C, C-4a,C-8a); 128.04, 127.63 (2C, C-5, C-8); 124.80 (1C, C-1′); IR (KBr): ν(cm⁻¹); 1691, 1674 (C═O).

EXAMPLE 102-(4-Chlorophenyl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]oxazole

To a solution of 5.0 g (24 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 60 mL of dioxane,one adds at ambient temperature 15.3 mL (120 mmol) of 4-chlorobenzoicacid chloride and 0.5 mL of concentrated sulfuric acid. The reactionmixture is heated to reflux for 4 h, then evaporated to dryness,redissolved in 200 mL of dichloromethane, and neutralized at coldtemperature with 100 mL of 10N sodium hydroxide. The organic phase isthen washed three times with water and dried over calcium chloride. Thered powder so obtained is purified on a flash column (support: silica;conditioning: heptane; eluant: dichloromethane/heptane, 70/30). Theyellow crystals obtained after evaporation of the solvent are uncoloredand recrystallized in dichloromethane to produce 2.5 g of2-(4-chlorophenyl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]oxazole in theform of yellow crystals.

Yield: 34%; Melting point: >260° C.; Rf: 0.40 (CH₂Cl₂/heptane, 80/20);MS (I.E.): m/z 309, 311 (MH+.); ¹H-NMR (CDCl₃): δ (ppm); 8.28 (m, 4H,H-5, H-8, H-2′, H-6′); 7.82 (m, 2H, H-6, H-7); 7.55 (d, 2H, H-3′, H-5′,J_(H2′-H3′)=J_(H5′-H6′)=8.34 Hz); ¹³C-NMR (CDCl₃): δ (ppm); 178.55,173.21 (2C, C-4, C-9); 165.31 (1C, C-2); 150.35, 144.03 (2C, C-3a,C-9a); 139.55 (1C, C-4′); 134.48, 134.43 (2C, C-6, C-7); 132.38, 132.04(2C, C-4a, C-8a); 129.65, 129.49 (4C, C-2′, C-3′, C-5′, C-6′); 127.55,127.09 (2C, C-5, C-8); 123.63 (1C, C-1′); IR (KBr): ν (cm⁻¹); 1695, 1675(C═O).

EXAMPLE 11 4,9-Dihydro-4,9-dioxo-2-(2-thienyl)-naphtho[2,3-d]oxazole

To a solution of 5.0 g (24 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 50 mL ofdichloromethane, one adds, with protection from light and at ambienttemperature, 12.9 mL (120 mmol) of 2-thenoyl acid chloride, then 3 μL ofconcentrated sulfuric acid. After 21 h of reflux, the reaction mixtureis evaporated to dryness and the black oily residue obtained isredissolved in 100 mL of dichloromethane and washed with a 10N sodiumhydroxide solution, then with water, and finally dried over calciumchloride. The product is then purified on a flash column (silica 6-35μm; conditioning: heptane; eluant: dichloromethane/heptane, 60/40), toproduce 5.3 g of4,9-dihydro-4,9-dioxo-2-(2-thienyl)naphtho[2,3-d]oxazole in the form ofyellow-orangish crystals after recrystallization and color removal withanimal charcoal.

Yield: 78%; Melting point: >260° C.; Rf: 0.41 (CH₂Cl₂); MS (I.E.): m/z281 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.22 (dd, 2H, H-5, H-8,J_(H5-H6)=8.85 Hz, J_(H5-H7)=1.73 Hz); 8.06 (dd, 1H, H-5′,J_(H5′-H4′)=3.49 Hz, J_(H5′-H3′)=1.00 Hz); 7.83 (m, 2H, H-6, H-7); 7.73(dd, 1H, H-3′, J_(H3′-H4′)=4.88 Hz, J_(H3′-H5′)=1.00 Hz); 7.27 (dd, 1H,H-4′, J_(H4′-H3′)=4.88 Hz, J_(H4′-H5′)=3.49 Hz); IR (KBr): ν (cm⁻¹);1687, 1667 (C═O).

EXAMPLE 124,9-Dihydro-4,9-dioxo-2-(2-fluorophenyl)-naphtho[2,3-d]thiazole

To a suspension of 5.0 g (24 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 80 mL of water, 8.4g (35 mmol) of nonahydrated sodium sulfide are added. The reactionmixture is then heated to reflux for approximately 20 min, then 20 mL ofan aqueous solution containing 2.0 g of sodium sulfide are added. Whenthe color of the medium has completely changed to blue, 1.95 mL (24mmol) of 2-fluorobenzaldehyde and 6.36 mL of glacial acetic acid areadded successively. After 1 h of reflux, the black semisolid productobtained is filtered, dried, and purified on a flash column (support:silica; conditioning: heptane; eluant: dichloromethane/heptane, 50/50).The greenish crystals formed after evaporation of the solvent are washedseveral times with ethanol and ether, then they are uncolored andrecrystallized in dichloromethane to produce 2.0 g of4,9-dihydro-4,9-dioxo-2-(2-fluorophenyl)-naphtho[2,3-d]thiazole in theform of yellow crystals.

Yield: 27%; Melting point: >260° C.; Rf: 0.60 (CH₂Cl₂); MS (I.E.): m/z309 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.62 (m, 1H, H-6′); 8.30, 8.21 (2dd,2H, H-5, H-8, J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H6-H8)=J_(H5-H7)=1.73 Hz);7.81 (m, 2H, H-6, H-7); 7.56 (m, 1H, H-4′); 7.29 (m, 2H, H-3′, H-5′);¹³C-NMR (CDCl₃): δ (ppm); 179.17 (2C, C-4, C-9); 169.20 (1C, C-2′);153.47 (1C, C-2); 134.43, 134.09 (2C, C-6, C-7); 133.70, 133.56 (2C,C-4a, C-8a); 130.02 (1C, C-6′); 127.86, 126.97 (2C, C-5, C-8); 124.99(1C, C-4′); 120.00 (1C, C-5′); 116.48, 115.90 (2C, C-1′, C-3′); IR(KBr): ν (cm⁻¹); 1683, 1661 (C═O).

EXAMPLE 134,9-Dihydro-4,9-dioxo-2-(3-fluorophenyl)-naphtho[2,3-d]thiazole

To a solution of 5.0 g (24 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 50 mL of water, asolution is added which contains 8.4 g (35 mmol) of nonahydrated sodiumsulfide in 50 mL of water. The reaction mixture is heated to reflux forapproximately 20 min. When the reaction medium turns blue, 2.50 mL (24mmol) of 3-fluorobenzaldehyde and 6.36 mL of glacial acetic acid areadded successively. After 2h of reflux, the black product obtained isfiltered, dissolved in dichloromethane, washed with distilled water,dried over calcium chloride, filtered, and evaporated at reducedpressure. The black-green solid obtained is then purified on a flashcolumn (support: silica; conditioning: heptane; eluant:dichloromethane/heptane, 50/50, then dichloromethane, thendichloromethane/methanol, 99/1). The solid obtained after evaporation ofthe solvent is washed several times with methanol, ethanol, and ether,then uncolored and recrystallized in dichloromethane to produce 4.0 g of4,9-dihydro-4,9-dioxo-2-(3-fluorophenyl)-naphtho[2,3-d]thiazole in theform of yellow crystals.

Yield: 54%; Melting point: >260° C.; Rf: 0.56 (CH₂Cl₂); MS (I.E.): m/z309 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.37, 8.25 (2dd, 2H, H-5, H-8,J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H6-H8)=J_(H5-H7)=1.73 Hz); 7.95 (m, 2H,H-2′, H-6′); 7.84 (m, 2H, H-6, H-7); 7.55 (m, 1H, H-5′); 7.25 (m, 1H,H-4′); IR (KBr): ν (cm⁻¹); 1676, 1661 (C═O).

EXAMPLE 144,9-Dihydro-4,9-dioxo-2-(4-fluorophenyl)naphtho[2,3-d]thiazole

To a suspension of 5.0 g (24 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 130 mL of water,8.4 g (35 mmol) of nonahydrated sodium sulfide are added. The reactionmixture is heated to reflux for 20 min, then 50 mL of an aqueoussolution containing 1.0 g of sodium sulfate are added. The color of themedium changes completely to blue. 2.60 mL (24 mmol) of4-fluorobenzaldehyde and 6.36 mL of glacial acetic acid are addedsuccessively. After 1 h of reflux, the greenish precipitate obtained isfiltered, dried, and purified on a flash column (support: silica;conditioning: heptane; eluant: dichloromethane/heptane, 60/40). Theyellow crystals formed after evaporation of the solvent are washedsuccessively with the isopropanol and ether, then uncolored andrecrystallized in dichloromethane to produce 2.0 g of4,9-dihydro-4,9-dioxo-2-(4-fluorophenyl)naphtho[2,3-d]thiazole in theform of yellow crystals.

Yield: 27%; Melting point: >260° C.; Rf: 0.51 (CH₂Cl₂/heptane, 90/10);MS (I.E.): m/z 309 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.30, 8.21 (2dd, 2H,H-5, H-8, J_(H5-H6)=J_(H8-H7)=8.85 Hz, J_(H5-H7)=J_(H8-H6)=1.73 Hz);8.12 (m, 2H, H-2′, H-6′); 7.83 (m, 2H, H-6, H-7); 7.22 (m, 2H, H-3′,H-5′); ¹³C-NMR (CDCl₃): δ (ppm); 179.17 (2C, C-4, C-9); 165.21 (1C,C-4′); 134.46, 134.04 (2C, C-6, C-7); 132.78, 132.43 (2C, C-4a, C-8a);130.08, 129.96 (2C, C-2′, C-6′); 127.88, 126.98 (2C, C-5, C-8); 116.74,116.42 (2C, C-3′, C-5′); IR (KBr): ν (cm⁻¹); 1678, 1659 (C═O).

EXAMPLE 152-(2,4-Difluorophenyl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole

To 5.0 g (24.15 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 150 mL of water,150 mL of an aqueous solution containing 29.0 g (120.00 mmol) ofnonahydrated sodium sulfide are added. The reaction mixture is heated toreflux for 20 min. The color of the medium changes completely to blue;2.0 mL (18.00 mmol) of 2,4-difluorobenzaldehyde and 6.3 mL of glacialacetic acid are added successively. After 3 h of reflux, the solidformed is filtered, washed in distilled water, dried, and purified on acake (support: silica; eluant: dichloromethane). The yellow crystalsobtained after evaporation of the solvents are recrystallized indichloromethane and uncolored with animal charcoal to produce 3.9 g of2-(2,4-difluorophenyl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole.

Yield: 97%; Melting point: >260° C.; Rf: 0.40 (CH₂Cl₂); MS (I.E.): m/z327 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.55 (m, 1H, H-3′); 8.28, 8.24 (2dd,2H, H-5, H-8, J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H5-H7)=J_(H6-H8)=1.73 Hz);7.84 (m, 2H, H-6, H-7); 7.10 (m, 2H, H-5′, H-6′); ¹³C-NMR (CDCl₃): δ(ppm); 178.88, 177.93 (2C, C-4, C-9); 163.45 (1C, C-2); 134.87, 134.52(2C, C-6, C-7); 133.44, 133.10, 131.61 (4C, C-3a, C-4a, C-8a, C-9a);127.95, 127.18 (2C, C-5, C-8); 123.45 (1C, C-1′); 113.53, 113.21 (2C,C-2′, C-4′); 105.56, 105.18, 104.79 (3C, C-3′, C-5′, C-6′); IR (KBr): ν(cm⁻¹); 1681, 1658 (C═O).

EXAMPLE 16 4,9-Dihydro-4,9-dioxo-2-(3-pyridyl)-naphtho[2,3-d]thiazole

To a suspension of 10.00 g (48.2 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 100 mL of water,13.88 g (74.5 mmol) of nonahydrated sodium sulfide are added. Thereaction mixture, which is gradually heated to reflux, changes to a bluecolor starting at 60° C. The addition of 4.00 g (16.7 mmol) ofconcentrated sodium sulfide in the water is necessary to complete thechange in color; 6 mL (60.6 mmol) of 3-pyridine carboxyaldehyde and 10mL of glacial acetic acid are then added successively. After 2 h ofreflux, and complete cooling, 300 mL of ethanol are added. Theprecipitate formed is eliminated by filtration. The filtrate isevaporated to dryness, redissolved in dichloromethane, washed severaltimes with ether, then with water, dried, and purified on amedium-pressure column (support: silica; conditioning: heptane; eluant:dichloromethane/methanol, 100/0 to 99/1). The yellow crystals formedafter evaporation of the solvent are washed with ethanol, thenuncolored, and recrystallized in dichloromethane to produce 1.00 g of4,9-dihydro-4,9-dioxo-2-(3-pyridyl)-naphtho[2,3-d]thiazole in the formof yellow crystals.

Yield: 7%; Melting point: 256° C.; Rf: 0.50 (CH₂Cl₂/methanol, 98/2); MS(I.E.): m/z 292 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 9.33 (d, 1H, H-2′,J=1.83 Hz); 8.80 (d, 1H, H-6′, J_(H5′-H6′)=3.36 Hz); 8.49 (d, 1H, H-4′,J_(H4′-H5′)=7.93 Hz); 8.36, 8.26 (2dd, 2H, H-5, H-8,J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H5-H7)=J_(H6-H8)=1.73 Hz); 7.84 (m, 2H,H-6, H-7); 7.50 (dd, 1H, H-5′, J_(H4′-H5′)=7.93 Hz, J_(H5′-H6′)=3.36Hz); 13C-NMR (CDCl₃): δ (ppm); 178.13, 177.78 (2C, C-4, C-9); 177.67(1C, C-2); 155.18 (1C, C-3a); 152.87, 148.58 (2C, C-2′, C-6′); 142.18(1C, C-9a); 134.77, 134.31 (2C, C-6, C-7); 134.18 (1C, C-4′); 132.74,132.01 (2C, C-4a, C-8a); 128.36 (1C, C-3′); 128.04, 127.16 (2C, C-5,C-8); 124.56 (1C, C-5′); IR (KBr): ν (cm⁻¹); 1680, 1660 (C═O).

EXAMPLE 17 4,9-Dihydro-4,9-dioxo-2-(4-pyridyl)-naphtho[2,3-d]thiazolesulfate

To a suspension of 500 mg (1.71 mmol) of4,9-dihydro-4,9-dioxo-2-(4-pyridyl)-naphtho[2,3-d]thiazole in 60 mL ofmethanol, 60 mL of a methanol solution containing 0.18 mL (1.74 mmol) of98% sulfuric acid are added. After 1 h of reflux and complete cooling,the yellow precipitate obtained is filtered, rinsed several times withethylic ether, and dried. In this manner, 500 mg of4,9-dihydro-4,9-dioxo-2-(4-pyridyl)-naphtho[2,3-d]thiazole sulfate areobtained, in the form of yellow crystals.

Yield: 75%; Melting point: >260° C.; Rf: 0.50 (CH₂Cl₂/methanol, 96/4);IR (KBr): ν (cm⁻¹); from 3100 and 2725 (NH⁺); 1686, 1668 (C═O).

EXAMPLE 18 4,9-Dihydro-4,9-dioxo-2-(3-furyl)naphtho[2,3-d]thiazole

To 6.0 g (29 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene,100 mL of a freshly prepared aqueous solution are added, which contains34.8 g (145 mmol) of nonahydrated sodium sulfide. The reaction mixtureis stirred at 70° C. for 20 min, until a blue coloration is obtained;2.5 mL (29 mmol) of 3-furaldehyde and 7.6 mL (133 mmol) of glacialacetic acid are then added successively. After 2h of stirring at 50° C.,then for 1 h 40 min at ambient temperature, the dark yellow precipitateobtained is filtered and washed two times with 500 mL of water. In thismanner, 7.0 g of crystals are obtained, which are redissolved in 500 mLof dichloromethane, washed three times with 750 mL of water, then driedover calcium chloride and filtered. After evaporation of thedichloromethane at reduced pressure, the orange crystals so obtained arepurified by filtration over a silica bed (dichloromethane/heptane,80/20) to produce 3.5 g of4,9-dihydro-4,9-dioxo-2-(3-furyl)naphtho[2,3-d]thiazole in the form ofyellow crystals, which are recrystallized in ethyl acetate after colorremoval with animal charcoal.

Yield: 43%; Melting point: 245° C.; Rf: 0.58 (CH₂Cl₂); MS (I.E.): m/z281 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.34 (dd, 1H, H-5 or H-8,J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H5-H7)=J_(H6-H8)=1.73 Hz); 8.28 (dd, 1H,H-2′, J_(H2′-H5′)=1.50 Hz, J_(H2′-H4′)=0.90 Hz); 8.23 (dd, 1H, H-5 orH-8, J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H5-H7)=J_(H6-H8)=1.73 Hz); 7.81 (m,2H, H-6, H-7); 7.56 (t, 1H, H-5′, J_(H2′-H5′)=1.50 Hz); 6.98 (dd, 1H,H-4′, J_(H2′-H4′)=0.90 Hz, J_(H4′-H5′)=1.80 Hz); ¹³C-NMR (CDCl₃): δ(ppm); 178.28, 177.83 (2C, C-4, C-9); 167.28 (1C, C-2); 155.05 (1C,C-3a); 144.77, 143.90 (2C, C-2′, C-5′); 140.77 (1C, C-9a); 134.39,134.06 (2C, C-6, C-7); 133.04, 132.63 (2C, C-4a, C-8a); 127.86, 126.90(2C, C-5, C-8); 120.80 (1C, C-3′); 109.19 (1C, C-4′); IR (KBr): ν(cm⁻¹); 1678, 1656 (C═O).

EXAMPLE 192-(5-Chloro-furan-2-yl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole

To a solution of 1.78 g (6.3 mmol) of4,9-dihydro-4,9-dioxo-2-(2-furyl)-naphtho[2,3-d]thiazole in 600 mL ofchloroform, gaseous chlorine is bubbled in at 0° C. for 2 min. Thereaction mixture is stirred for an additional 10 min, until a lightyellow solution is obtained. The excess chlorine is then eliminated bypassing an argon flow. The yellow solid obtained after evaporation atreduced pressure is then purified on a flash column (silica 6-35 μm;conditioning: heptane; eluant: dichloromethane/heptane, 50/50) toproduce 0.43 g of pale yellow crystals. After filtration on a silicabed, 0.40 g of2-(5-chlorofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole isobtained in the form of yellow crystals after recrystallization andcolor removal with animal charcoal.

Yield: 20%; Melting point: 257.7° C.; Rf: 0.42 (CH₂Cl₂); MS (I.E.): m/z315 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.33 (dd, 1H, H-5 or H-8,J_(H5-H6)=8.85 Hz, J_(H5-H7)=1.73 Hz); 8.23 (dd, 1H, H-5 or H-8,J_(H5-H6)=8.85 Hz, J_(H5-H7)=1.73 Hz); 7.81 (m, 2H, H-6, H-7); 7.43 (d,1H, H-3′, J_(H3′-H4′)=3.58 Hz); 6.45 (d, 1H, H-4′, J_(H3′-H4′)=3.58 Hz);¹³C-NMR (CDCl₃): δ (ppm); 178.10, 177.92 (2C, C-4, C-9); 163.94 (1C,C-2); 141.10 (1C, C-2′); 140.78 (1C, C-3a); 139.58 (1C, C-9a); 134.40,134.17 (2C, C-6, C-7); 133.10, 132.68 (2C, C-4a, C-8a); 127.86, 126.95(2C, C-5, C-8); 115.65 (1C, C-3′); 113.34 (1C, C-4′); IR (KBr): ν(cm⁻¹); 1678, 1652 (C═O).

EXAMPLE 20 4,9-Dihydro-4,9-dioxo-2-(2-thienyl)-naphtho[2,3-d]thiazole

To 4.00 g (19 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene, 150 mL of a freshlyprepared aqueous solution containing 22.80 g (95 mmol) of nonahydratedsodium sulfide are added. The reaction mixture is heated at 80° C. for20 min, until a blue coloration is obtained; 1.8 mL (19 mmol) of2-thiophene carboxyaldehyde and 5.0 mL (87 mmol) of glacial acetic acidare then added successively. After 2 h of stirring, the black-chestnutbrown precipitate obtained is filtered, then dissolved in 350 mL ofdichloromethane. The organic phase is washed three times with 150 mL ofwater, dried over calcium chloride, and filtered. The orange solidobtained after evaporation of the dichloromethane at reduced pressure isuncolored with animal charcoal and recrystallized in dichloromethane toproduce 2.71 g of4,9-dihydro-4,9-dioxo-2-(2-thienyl)naphtho[2,3-d]thiazole in the form ofred-orangish crystals.

Yield: 48%; Melting point: >260° C.; Rf: 0.58 (CH₂Cl₂); MS (I.E.): m/z297 (MH+.); ¹H-NMR (CDCl₃): δ (ppm); 8.32 (dd, 1H, H-5 or H-8,J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H5-H7)=J_(H6-H8)=1.73 Hz); 8.21 (dd, 1H,H-5 or H-8, J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H5-H7)=J_(H6-H8)=1.73 Hz);7.82 (m, 3H, H-6, H-7, H-5′); 7.62 (dd, 1H, H-3′, J_(H3′-H4′)=4.88 Hz,J_(H3′-H5′)=1.00 Hz); 7.18 (dd, 1H, H-4′, J_(H3′-H4′)=4.88 Hz,J_(H4′-H5′)=3.49 Hz); ¹³C-NMR (CDCl₃): δ (ppm); 178.32, 177.92 (2C, C-4,C-9); 169.34 (1C, C-2); 155.14 (1C, C-3a); 135.50 (1C, C-9a); 134.37,134.02 (2C, C-6, C-7); 132.78, 132.43 (2C, C-4a, C-8a); 130.19 (1C,C-4′); 128.50 (1C, C-3′); 127.84, 127.61 (2C, C-5, C-8); 126.86 (C-5′);IR (KBr): ν (cm⁻¹); 1676, 1654 (C═O).

EXAMPLE 21 4,9-Dihydro-4,9-dioxo-2-(3-thienyl)-naphtho[2,3-d]thiazole

To 4.0 g (19 mmol) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene,90 mL of a freshly prepared aqueous solution containing 22.8 g (95 mmol)of nonahydrated sodium sulfide are added. The reaction mixture is heatedat 90° C. for 20 min, until a blue coloration is obtained; 1.8 mL (19mmol) of 3-thiophene carboxyaldehyde and 5.0 mL (87 mmol) of glacialacetic acid are then added successively. After 2 h of stirring at 90°C., the yellow-greenish precipitate obtained is filtered, washed threetimes with 400 mL of water, and dried. The crystals are redissolved in200 mL of isopropanol, stirred at ambient temperature for 1 h, thenfiltered, dried, and recrystallized in dichloromethane after colorremoval with animal charcoal to produce 4.0 g of4,9-dihydro-4,9-dioxo-2-(3-thienyl)-naphtho[2,3-d]thiazole in the formof yellow-ocher crystals.

Yield: 70%; Melting point: 258° C.; Rf: 0.55 (CH₂Cl₂/methanol,95.5/0.5); MS (I.E.): m/z 297 (MH+.); ¹H-NMR (CDCl₃): δ (ppm); 8.37 (dd,1H, H-5 or H-8, J_(H5-H6) ou J_(H7-H8)=8.85 Hz, J_(H5-H7) ouJ_(H6-H8)=1.73 Hz); 8.23 (m, 2H, H-5 or H-8, H-2′); 7.81 (m, 2H, H-6,H-7); 7.71 (d, 1H, H-5′, J_(H4′-H5′)=4.88 Hz); 7.48 (dd, 1H, H-4′,J_(H4-H5′)=4.88 Hz, J_(H2′-H4′)=2.99 Hz); ¹³C-NMR (CDCl₃): δ (ppm);178.32, 177.92 (2C, C-4, C-9); 169.34 (1C, C-2); 155.14 (1C, C-3a);140.69 (1C, C-9a); 134.36, 134.04 (2C, C-6, C-7); 133.09, 132.71 (2C,C-4a, C-8a); 128.23 (1C, C-4′); 127.84 (1C, C-5′); 127.61, 126.89,126.59 (3C, C-5, C-8, C-2′); IR (KBr): ν (cm⁻¹); 1674, 1655 (C═O).

EXAMPLE 22 4,9-Dihydro-4,9-dioxo-2-phenylamino-naphtho[2,3-d]thiazole

To a solution of 200 mg (0.8 mmol) of2-chloro-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole in 100 mL ofethanol, 730 μL (8 mmol) of aniline are added at 80° C. The reactionmixture is heated to reflux for 3.5 h; the red precipitate obtained isfiltered after cooling, then purified on a cake (support: silica 6-35μm; eluant: dichloromethane/heptane, 20/80 to 100/0, thendichloromethane/ethyl acetate, 99.5/0.5 to 0/100). The clean fractionsare combined, then filtered through micropores; the solvent isevaporated at reduced pressure to produce 196 mg of4,9-dihydro-4,9-dioxo-2-phenylamino-naphtho[2,3-d]thiazole in the formof red crystals.

Yield: 80%; Melting point: >260° C.; Rf: 0.44 (CH₂Cl₂/ethyl acetate,90/10); MS (I.E.): m/z 306 (M+.); ¹H-NMR (DMSO d₆): δ (ppm); 11.34 (s,1H, NH); 8.09 (m, 2H, H-5, H-8); 7.86 (m, 2H, H-6, H-7); 7.70 (m, 2H,H-2′, H-6′); 7.44 (m, 2H, H-3′, H-5′); 7.14 (m, 1H, H-4′); ¹³C-NMR (DMSOd₆): δ (ppm); 178.04, 177.31 (2C, C-4, C-9); 167.72 (1C, C-2); 154.61(1C, C-3a); 145.95 (1C, C-9a); 139.49 (1C, C-1′); 134.02, 133.93 (2C,C-6, C-7); 132.79, 132.06 (2C, C-4a, C-8a); 129.36 (2C, C-3′, C-5′);126.76, 125.73 (2C, C-5, C-8); 123.68 (1C, C-4′); 118.60 (2C, C-2′,C-6′); IR (KBr): ν (cm⁻¹); 3228 (NH); 1677, 1632 (C═O).

EXAMPLES 23 AND 244,9-Dihydro-4,9-dioxo-8-methoxy-2-phenyl-naphtho[2,3-d]thiazole and4,9-Dihydro-4,9-dioxo-5-methoxy-2-phenyl-naphtho[2,3-d]thiazole

Synthesis Intermediates:

1,4-Dihydro-1,4-dioxo-5-methoxy-naphthalene

To a solution of 26.45 g (0.147 mol) of1,4-dihydro-1,4-dioxo-5-hydroxynaphthalene in 1300 mL ofdichloromethane, one adds dropwise 39 mL (0.303 mol) of iodomethane,then 73.50 g of silver oxide. The reaction mixture is stirred for 72 h,then filtered. The filtrate is dried over calcium chloride, thenevaporated at reduced pressure. 28.50 g of orange crystals are produced,which are purified on a cake (support: silica 40-60 mm; eluant:heptane/ethyl acetate, 70/30 to 0/100) to produce 23.80 g of1,4-dihydro-1,4-dioxo-5-hydroxynaphthalene.

Yield: 86%; Melting point: 188° C.; Rf: 0.50 (Ethyl acetate/heptane,50/50); ¹H-NMR (CDCl₃): δ (ppm); 7.72 (m, 2H, H-6, H-8); 7.32 (dd, 1H,H-7, J_(H6-H7)=J_(H7-H8)=7.63 Hz); 6.88 (m, 2H, H-2, H-3); 4.01 (s, 3H,OCH₃).

2,3-Dibromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene

To a solution of 3.5 g (18.6 mmol) of1,4-dihydro-1,4-dioxo-5-methoxynaphthalene in 135 mL of chloroform, 3.05g (37.2 mmol) of sodium acetate and 3 mL (58.4 mmol) of bromine areadded. The reaction medium is stirred for 48 h. The acetate salts formedare filtered. The filtrate is washed with distilled water, dried overcalcium chloride, then evaporated at reduced pressure to produce 7.3 gof 1,4-dihydro-1,4-dioxo-2,3-dibromo-5-methoxynaphthalene in the form oforange crystals.

Yield: 100%; Melting point: 190° C.; ¹H-NMR (DMSO d₆): δ (ppm); 7.80(dd, 1H, H-8, J_(H7-H8)=7.85 Hz, J_(H6-H8)=1.53 Hz); 7.73 (dd, 1H, H-7,J_(H6-H7)=8.34 Hz, J_(H6-H8)=7.85 Hz); 7.37 (m, 1H, H-6); 3.95 (s, 3H,OCH₃).

2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene and

2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene

To a solution of 500.0 mg (1.5 mmol) of2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene in 25 mL oftetrahydrofuran, a drop of ammonia is added. The color of the reactionmedium turns black. A current of ammonia is passed through the mediumfor 2 h at 20° C. The raw product obtained after evaporation of thesolvent is purified on cake (support: silica; eluant:dichloromethane/heptane, 80/20) to produce 347.3 g of a mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene and2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene.

Overall Yield: 82%

2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene

¹H-NMR (DMSO d₆): δ (ppm); 7.78 (d, 1H, H-8, J_(H7-H8)=7.94 Hz); 7.67(dd, 1H, H-7, J_(H6-H7)=8.54 Hz, J_(H7-H8)=7.94 Hz); 7.25 (d, 1H, H-6,J_(H6-H7)=8.54 Hz); 3.99 (s, 3H, OCH₃); 1.73 (s, 2H, NH₂).

2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene

¹H-NMR (DMSO d₆): δ (ppm); 7.73 (d, 1H, H-8, J_(H7-H8)=8.57 Hz); 7.61(t, 1H, H-7, J_(H7-H6)=J_(H7-H8)=8.57 Hz); 7.34 (d, 1H, H-6,J_(H6-H7)=8.57 Hz); 3.97 (s, 3H, OCH₃); 1.73 (s, 2H, NH₂).

4,9-Dihydro-4,9-dioxo-8-methoxy-2-phenylnaphtho[2,3-d]thiazole

(Example 23) and4,9-dihydro-4,9-dioxo-5-methoxy-2-phenyl-naphtho[2,3-d]thiazole (Example24)

To a solution of 93.70 g (389.00 mmol) of nonahydrated sodium sulfide in400 mL of water, 18.30 g (64.87 mmol) of a (1/1) mixture of2-amino-3-bromo-5-methoxy-1,4-dihydro-1,4-dioxo-naphthalene and2-amino-3-bromo-8-methoxy-1,4-dihydro-1,4-dioxonaphthalene are added.The reaction medium is heated to reflux until a blue coloration isobtained; 6.6 mL (64.87 mmol) of benzaldehyde are added, then 22.3 mL ofglacial acetic acid are added dropwise successively. After 1 h ofreflux, and complete cooling, the precipitate obtained is filtered,washed with ethanol, and redissolved in chloroform. The organic phase iswashed with water, then dried over calcium chloride; 16.50 g of yellowcrystals are produced after evaporation of the solvents at reducedpressure, then they are purified on a flash column (support: silica40-60 mm; eluant: dichloromethane/ethyl acetate, 100/0 to 97/3) toproduce, after color removal and recrystallization in dichloromethane,8.90 g of 4,9-dihydro-4,9-dioxo-8-methoxy-2-phenylnaphtho[2,3-d]thiazole(Example 23) and 2.29 g of4,9-dihydro-4,9-dioxo-5-methoxy-2-phenylnaphtho[2,3-d]thiazole (Example24) in the form of yellow crystals.

4,9-Dihydro-4,9-dioxo-8-methoxy-2-phenylnaphtho[2,3-d]thiazole (Example23)

Yield: 42%; Melting point: >260° C.; Rf: 0.55 (CH₂Cl₂/ethyl acetate,90/10); MS (I.E.): m/z 321 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.14 (dd, 2H,H-2′, H-6′, J_(H2′-H3′)=J_(H5′-H6′)=6.10 Hz,J_(H2′-H4′)=J_(H4′-H6′)=1.80 Hz); 7.90 (d, 1H, H-5, J_(H5-H6)=7.63 Hz);7.73 (dd, 1H, H-6, J_(H5-H6)=7.60 Hz, J_(H6-H7)=8.50 Hz); 7.52 (m, 3H,H-3′, H-4′, H-5′); 7.39 (d, 1H, H-7, J_(H6-H7)=8.50 Hz); 4.06 (s, 3H,OCH₃); ¹³C-NMR (CDCl₃): δ (ppm); 177.95 (1C, C-9); 177.58 (1C, C-4);161.00 (1C, Cquat); 135.98 (1C, Cquat); 135.01 (1C, C-6); 132.23 (1C,C-4′); 129.20 (2C, C-3′, C-5′); 127.79 (2C, C-2′, C-6′); 119.78, 119.02(2C, C-5, C-7); 56.74 (OCH₃); IR (KBr): ν (cm⁻¹); 1671 (C═O).

4,9-Dihydro-4,9-dioxo-5-methoxy-2-phenylnaphtho[2,3-d]thiazole (Example24)

Yield: 11%; Melting point: 245° C.; Rf: 0.47 (CH₂Cl₂/ethyl acetate,98/2); MS (I.E.): m/z 321 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.15 (dd, 2H ,H-2′, H-6′, J_(H2′-H3′)=J_(H5′-H6′)=7.98 Hz,J_(H2′-H4′)=J_(H4′-H6′)=1.90 Hz); 7.92 (d, 1H, H-8, J_(H7-H8)=7.60 Hz);7.73 (t, 1H, H-7, J_(H7-H8)=J_(H6-H7)=8.00 Hz); 7.53 (m, 3H, H-3′, H-4′,H-5′); 7.39 (d, 1H, H-6, J_(H6-H7)=8.00 Hz); 4.03 (s, 3H, OCH₃); ¹³C-NMR(CDCl₃): δ (ppm); 161.50 (1C, C-5); 135.50 (1C, Cquat); 135.08 (1C,C-7); 132.20 (1C, C-4′); 129.70 (2C, C-3′, C-5′); 127.80 (2C, C-2′,C-6′); 119.75 (1C, C-6); 119.02 (1C, C-8); 57.00 (1C, OCH₃); IR (KBr): ν(cm⁻¹); 1678, 1651 (C═O).

EXAMPLES 25 AND 264,9-Dihydro-4,9-dioxo-7-methoxy-2-phenylnaphtho[2,3-d]thiazole and4,9-Dihydro-4,9-dioxo-6-methoxy-2-phenylnaphtho[2,3-d]thiazole

To a solution of 9.9 g (41.0 mmol) of nonahydrated sodium sulfide in 27mL of water, 1.9 g (6.7 mmol) of a (1/1) mixture of2-amino-3-bromo-6-methoxy-1,4-dihydro-1,4-dioxonaphthalene and3-amino-2-bromo-6-methoxy-1,4-dihydro-1,4-dioxonaphthalene are added.The reaction mixture is then heated at 50° C. until a blue coloration isobtained; 0.685 mL (6.7 mmol) of benzaldehyde and 2.300 mL of glacialacetic acid are then added successively. After 3 h of heating andcomplete cooling, the green crystals obtained are filtered, washed withethanol, and dissolved in 300 mL of chloroform. The organic phase iswashed with 100 mL of water, dried over calcium chloride, and evaporatedat reduced pressure. 4.0 g of yellow crystals are produced, which arepurified on a medium-pressure chromatography column (support: silica6-35 mm, internal diameter: 3.0 cm, height: 40 cm, pressure: 30 bar,eluant: heptane/dichloromethane, 100/0 to 65/35). The yellow crystalsobtained are uncolored and recrystallized in dichloromethane to produce0.2 g of 4,9-dihydro-4,9-dioxo-7-methoxy-2-phenylnaphtho[2,3-d]thiazole(Example 25) and 1.2 g of4,9-dihydro-4,9-dioxo-6-methoxy-2-phenylnaphtho[2,3-d]thiazole (Example26).

4,9-Dihydro-4,9-dioxo-7-methoxy-2-phenylnaphtho[2,3-d]thiazole (Example25)

Yield: 1.5%; Melting point: >260° C.; Rf: 0.47 (CH₂Cl₂); MS (I.E.): m/z321 (M+.); ¹H-NMR (270 MHZ, CDCl₃): δ (ppm); 8.20 (s, 1H, H-8); 8.15(dd, 2H, H-2′, H-6′, J_(H2′-H3′)=J_(H5′-H6′)=7.21 Hz,J_(H2′-H4′)=J_(H4′-H6′)=1.93 Hz); 7.78 (d, 1H, H-5, J_(H5-H6)=8.65 Hz);7.53 (m, 3H, H-3′, H-4′, H-5′); 7.24 (d, 1H, H-6, J_(H5-H6)=8.65 Hz);4.01 (s, 3H, OCH₃); ¹³C-NMR (270 MHZ, CDCl₃): δ (ppm); 132.68 (1C, C-5);129.84 (1C, C-4′); 129.69 (2C, C-3′, C-5′); 128.20 (2C, C-2′, C-6′);120.64 (1C, C-6); 111.99 (1C, C-8); 56.58 (OCH₃ ); IR (KBr): ν (cm⁻¹);1679 (C═O).

4,9-Dihydro-4,9-dioxo-6-methoxy-2-phenylnaphtho[2,3-d]thiazole (Example26)

Yield: 9%; Melting point: 221° C.; Rf: 0.65 (CH₂Cl₂/ethyl acetate,98/2); MS (I.E.): m/z 321 (M+.); ¹H-NMR (270 MHZ, CDCl₃): δ (ppm); 8.29(d, 1H, H-8, J_(H7-H8)=8.65 Hz); 8.14 (d, 2H, H-2′, H-6′,J_(H2′-H3′)=J_(H5′-H6′)=7.21 Hz); 7.67 (d, 1H, H-5, J_(H5-H7)=2.67 Hz);7.52 (m, 3H, H-3′, H-4′, H-5′); 7.25 (dd, 1H, H-7, J_(H7-H8)=8.65 Hz,J_(H5-H7)=2.67 Hz); 4.01 (s, 3H, OCH₃); ¹³C-NMR (270 MHZ, CDCl₃): δ(ppm); 164.21 (1C, C-6) 155.88 (1C, Cquat); 135.87 (1C, Cquat); 132.31(1C, C-5); 130.30 (1C, C-4′); 129.25 (2C, C-3′, C-5′); 127.79 (2C, C-2′,C-6′); 127.40 (1C, Cquat); 120.27 (1C, C-7); 110.09 (1C, C-8); 56.05(OCH₃ ); IR (KBr): ν (cm⁻¹); 1667 (C═O).

EXAMPLE 274,9-Dihydro-4,9-dioxo-8-hydroxy-2-phenyl-naphtho[2,3-d]thiazole

A suspension of 1.00 g (0.003 mol) of4,9-dihydro-4,9-dioxo-8-methoxy-2-phenyl-naphtho[2,3-d]-thiazole(Example 23) in 67 mL (1.160 mol) of acetic acid and 67 mL (0.570 mol)of hydrobromic acid is heated to reflux for 5 h 30 min. After cooling to10° C., the reaction medium is filtered through fritted glass. Theprecipitate consists of 200 mL of chloroform. The organic phase iswashed with a 3% ammonia solution (3×40 mL) and dried over calciumchloride. The yellow solid obtained after evaporation at reducedpressure of the solvent is purified on a medium-pressure column(support: silica 6-35 mm, eluant: toluene/dichloromethane, 100/0, 50/50,0/100), then recrystallized 3 times in a toluene/heptane mixture, 50/50,to produce 0.302 g of4,9-dihydro-4,9-dioxo-8-hydroxy-2-phenyl-naphtho[2,3-d]thiazole.

Yield: 33%; Melting point: 263.5° C.; Rf: 0.51 (heptane/ethyl acetate,70/30); MS (I.E.): m/z 307 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.08 (dd, 2H,H-2′, H-6′, J_(H2′-H3′)=J_(H5′-H6′)=8.4 Hz, J_(H2′-H4′)=J_(H4′-H6′)=1.4Hz); 7.81 (dd, 1H, H-5, J_(H5-H7)=7.6 Hz, J_(H5-H6)=1.4 Hz); 7.67 (t,1H, H-7); 7.55 (m, 3H, H-3′, H-4′, H-5′); 7.35 (dd, 1H, H-6,J_(H6-H7)=8.4 Hz); ¹³C-NMR (CDCl₃): δ (ppm); 163.11 (1C, C-8); 136.57(1C, C-6); 132.53 (1C, C-4′); 129.32 (2C, C-3′, C-5′); 127.75 (2C, C-2′,C-6′); 125.62 (1C, C-7); 120.17 (1C, C-5); IR (KBr): ν (cm⁻¹); 1650(C═O).

EXAMPLE 28 4,9-Dihydro-4,9-dioxo-2-(1-pyrrolyl)-naphtho-[2,3]-thiazole

To a suspension of 2.30 g (0.01 mol) of2-amino-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole in 25 mL of aceticacid, 1.3 mL (0.01 mol) of hot 2,5-dimethoxytetrahydrofuran are added.The reaction mixture is heated to reflux for 2 h. The chestnut brownprecipitate obtained is filtered, dissolved in dichloromethane, andwashed 3 times with 200 mL of distilled water. The organic phase isdried over calcium chloride, filtered, and evaporated at reducedpressure to produce 1.80 g of a yellow solid, which is purified on aflash column (support: silica 6-35 mm; conditioning: heptane; eluant:dichloromethane/heptane, 90/10). 0.90 g of4,9-dihydro-4,9-dioxo-2-(1-pyrrolyl)-naphtho[2,3]-thiazole is obtainedin the form of yellow crystals after recrystallization and color removalwith animal black.

Yield: 64%; Melting point: >260° C.; Rf: 0.41 (CH₂Cl₂); MS (I.E.): m/z280 (M+.); ¹H-NMR (CDCl₃): δ (ppm); 8.29, 8.20 (2dd, 1H, H-5, H-8,J_(H5-H6)=8.85 Hz, J_(H5-H7)=1.73 Hz); 7.79 (m, 2H, H-6, H-7); 7.48 (m,2H, H-2′, H-5′); 6.42 (m, 2H, H-3′, H-4′); ¹³C-NMR (CDCl₃): δ (ppm);177.89, 177.47 (2C, C-4, C-9); 165.60 (1C, C-2); 153.00 (1C, C-3a);137.14 (1C, C-9a); 134.30, 134.06 (2C, C-6, C-7); 132.87, 132.38 (2C,C-4a, C-8a); 127.75, 126.69 (2C, C-5, C-8); 120.52 (2C, C-2′, C-5′);114.23 (2C, C-3′, C-4′); IR (KBr): ν (cm⁻¹); 1680, 1665 (C═O).

EXAMPLES 29 AND 302-(5-Bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho-[2,3-d]thiazole2-(4,5-Dibromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole

10.0 g (35.6 mmol, 1 eq) of4,9-dihydro-4,9-dioxo-2-(furan-2-yl)naphtho[2,3-d]thiazole are dissolvedin 750 mL of dichloromethane that has first been dried on a molecularmesh. The solution is cooled to 0° C., then 11.2 g (81.9 mmol, 2.3 eq)of aluminum chloride are added in small fractions.

The reaction mixture is heated to reflux, 8.0 mL (126.0 mmol, 3.5 eq) ofbromine dissolved in 20 mL of dichloromethane are added dropwise, andthe reaction is continued for 5 h. The solution is cooled, then gentlypoured into a saturated solution of sodium hydrogen carbonate. Theorganic phase is washed several times with water until the pH isneutral, then it is dried over calcium chloride.

10.5 g of solid raw product (chestnut brown-orangish) are obtained afterevaporation of the solvent; this is then purified on a flash column(support: silica 6-35 μm; eluant: CH₂Cl₂/heptane: 50/50, CH₂Cl₂: 80/20),to produce, after evaporation, 4.5 g of2-(5-bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]-thiazole inthe form of orange crystals and 380 mg of2-(4,5-dibromofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole,in the form of yellow crystals.

2-(5-Bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho-[2,3-d]thiazole

Yield: 42.8%; Melting point: >260° C.; Rf: 0.47 (CH₂Cl₂); MS (I.E): m/z359-361 (M⁺); ¹H-NMR (CDCl₃): δ (ppm); 8.34 (m, 1H, H-5 or H-8); 8.23(m, 1H, H-5 or H-8); 7.81 (m, 2H, H-6, H-7); 7.40 (d, 1H, H-3′,J_(H3′-H4′)=3.74 Hz); 6.59 (d, 1H, H-4′, J_(H3′-H4′)=3.67 Hz); ¹³C-NMR(CDCl₃): δ (ppm); 178.28, 177.99 (2C, C-4, C-9); 162.67 (C-2); 162.06(C-2′); 155.35 (C-3a); 149.88 (C-9a); 140.88 (C-5′); 134.58, 134.27 (2C,C-6, C-7); 133.30, 132.83 (2C, C-4a, C-8a); 127.24, 127.13 (2C, C-5,C-8); 115.23, 115.50 (2C, C-3′, C-4′); IR (KBr): ν (cm⁻¹); 1682 and 1656(C═O).

2-(4,5-Dibromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole

Yield: 2.4%; Melting point: >260° C.; Rf: 0.63 (CH₂Cl₂); MS (APcI−): m/z438 (M−H) ¹H-NMR (CDCl₃): δ (ppm); 8.35 (m, 1H, H-5 or H-8); 8.24 (m,1H, H-5 or H-8); 7.82 (m, 2H, H-6, H-7); 7.46 (s, 1H, H-3′); ¹³C-NMR(CDCl₃): δ [“d” earlier] (ppm); 134.54, 134.25 (2C, C-6, C-7); 127.92,127.03 (2C, C-5, C-8); 117.59 (1C, C-3′); IR (KBr): ν (cm⁻¹); 1685 and1655 (C═O).

EXAMPLE 312-(3-Bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho-[2,3-d]thiazole

To 150 mL of a solution of sodium hydroxide (pH 10.7), 5.33 g (22.2mmol, 1 eq) of nonahydrated sodium sulfide are added. The solution isheated at 90° C. and is stirred under an argon atmosphere. 4.61 g (22.2mmol, 1 eq) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene areadded, then the solution is stirred until a blue coloration is obtained.The solution is cooled to 20 and 25° C., then 3.89 g (22.2 mmol) of3-bromo-2-furaldehyde (CAS No. 14757-78-9) are added to the reactionmedium. After 5 min, the argon bubbling is replaced with compressed airfor 1 h, then 5 mL of acetic acid are added dropwise; the medium becomeschestnut brown-red.

The stirring is maintained for 5 min, the black precipitate formed isfiltered through fritted glass, washed with water, and dried to produce9.30 g of product, which are purified several times in a flash column(support: silica 6-35 μm; 4.5 cm φ, 30 cm h eluant:dichloromethane/heptane: 50/50).

After evaporation of the solvent, 2.15 g of2-(3-bromo-2-furan-2-yl)-4,9-dihydro-4,9-dioxo-naphtho-[2,3-d]thiazoleare produced in the form of orange crystals.

Yield: 26.9%; Melting point: >250° C.; Rf: 0.30 (CH₂Cl₂); MS (APcI+):m/z 361 (M⁺H⁺); ¹H-NMR (CDCl₃): δ (ppm); 8.36 (m, 1H, H-5 or H-8); 8.25(m, 1H, H-5 or H-8); 7.82 (m, 2H, H-6, H-7); 7.65 (d, 1H, H-5′,J_(H4′-H5′)=2.14 Hz); 6.75 (d, 1H, H-4′, J_(H4′-H5′)=2.14 Hz); ¹³C-NMR(DMSO-d₆): δ (ppm); 147.95 (1C, C-5′); 134.82, 134.42 (2C, C-6, C-7);127.24, 126.44 (2C, C-5, C-8); 117.50 (1C, C-4′); IR (KBr): ν (cm⁻¹);1680 and 1655 (C═O).

EXAMPLE 322-(4-Bromofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho-[2,3-d]thiazole

To 0.257 g (1.24 mmol, 1 eq) of2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphtalene in 9 mL of water, 1.19g (4.96 mmol, 4 eq) of nonahydrated sodium sulfide are added. Themixture is heated to reflux until the coloration of the reaction mediumhas turned completely blue. 0.26 g (1.48 mmol, 1.19 eq) of4-bromo-2-furaldehyde is then added to 90° C. The reaction medium isthen cooled to ambient temperature before the addition of 0.28 mL ofacetic acid. A precipitate then forms. The reaction medium is stirredfor 1 h at ambient temperature. The precipitate is filtered, then washedwith water. The chestnut brown precipitate (0.35 g) is purified on aflash column (support: alumina; conditioning: dichloromethane/heptane70/30; eluant: dichloromethane/heptane 70/30, then 80/20, then 100/00;then dichloromethane/methanol 99.6/0.4) to produce 0.145 g of2-(4-bromofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole in theform of orange crystals.

Yield: 32%; Melting point: >260° C.; Rf: 0.23 (dichloromethane/heptane,proportion 70/30) on an alumina support; MS (IE): m/z 360 (M⁺)^(·);¹H-NMR (CDCl₃): δ (ppm); 8.34 (m, 1H, H-5 or H-8); 8.25 (m, 1H, H-8 orH-5); 7.83 (m, 2H, H-6, H-7); 7.64 (d, 1H, H-5′, J_(H3′-H5′)=0.95 Hz);7.46 (d, 1H, H-3′, J_(H3′-H5′)=0.95 Hz); ¹³C-NMR (CDCl₃): δ (ppm);143.76 (1C, C-5′); 134.48, 134.17 (2C, C-6, C-7); 127.89, 126.99 (2C,C-5, C-8); 116.07 (1C, C-3′); IR (KBr): ν (cm⁻¹); 1680, 1657 (C═O).

EXAMPLE 334,9-Dihydro-4,9-dioxo-2-(5-nitrofuran-2-yl)naphtho-[2,3-d]thiazole

To 5 g (17.8 mmol) of4,9-dihydro-4,9-dioxo-2-(furan-2-yl)naphtho[2,3-d]thiazole, one adds 20mL of fuming nitric acid and 20 mL of concentrated sulfuric acid at roomtemperature. The reaction mixture is heated to reflux for 72 h; theprecipitate formed is filtered through fritted glass, washed with water,and rinsed with ether. The dark yellow powder obtained is recrystallizedin DMF after color removal with animal black. In this manner, 2 g of4,9-dihydro-4,9-dioxo-2-(5-nitro-furan-2-yl)naphtho-[2,3-d]thiazole areproduced in the form of a dark yellow solid.

Yield: 34%; Melting point: >300° C.; Rf: 0.30 (CH₂Cl₂); MS (APcI−): m/z326 (M⁻); ¹H-NMR (CDCl₃): δ (ppm); 8.39 (m, 1H, H-5 or H-8); 8.27 (m,1H, H-5 or H-8); 7.85 (m, 2H, H-6, H-7); 7.59 (d, 1H, H-4′,J_(H3′-H4′)=3.73 Hz); 7.50 (d, 1H, H-3′, J_(H3′-H4′)=3.74 Hz); IR (KBr):ν (cm⁻¹); 1675, 1656 (C═O).

EXAMPLE 342-(5-Aminofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho-[2,3-d]thiazole

In a three-necked flask, 2 g (6.10 mmol, 1 eq) of4,9-dihydro-4,9-dioxo-2-(5-nitrofuran-2-yl)-naphtho[2,3-d]-thiazole aredissolved in 1500 mL of absolute ethanol. The setup is placed under aninert atmosphere, and a spatula tip of 30% palladium-type charcoal isadded. The solution is heated to reflux and 360 μL (7.36 mmol; 1.2 eq)of hydrazine are added in five aliquots. The reaction is continued for 1h, with the solution's color changing from yellow-green to black-violet.The solution is cooled and filtered through Celite; 1.65 g of a blacksolid are obtained after evaporation of the solvent in a rota vapor.This solid is purified on a flash column (support: silica 6-35 μm,eluant gradient: dichloromethane, then dichloromethane/methanol, 98/2),to produce 0.36 g of2-(5-aminofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazole inthe form of blue crystals.

Yield: 20%; Melting point: >260° C.; Rf: 0.29 (Dichloromethane/ethylacetate, 99/1); MS (APcI+): m/z 297 (M⁺H⁺); ¹H-NMR (DMSO-d₆): δ (ppm);8.24 (m, 1H, H-5 or H-8); 8.18 (m, 1H, H-5 or H-8); 7.99 (m, 2H, H-6,H-7); 7.60 (d, 1H, H-3′, J_(H3′-H4′)=3.97 Hz); 7.36 (s, 2H, NH₂); 5.47(d, 1H, H-4′, J_(H3′-H4′)=3.97 Hz); ¹³C-NMR (DMSO-d₆): δ (ppm); 177.8,177.2 (2C, C-4, C-9); 161.0 (1C, C-5′); 155.0 (1C, C-2); 138.0 (1C,C-2′); 134.3, 134.1 (2C, C-6, C-7); 133.1, 132.4 (2C, C-4a, C-8a);127.0, 126.0 (2C, C-5, C-8); 122.1 (1C, C-3′); 87.5 (1C, C-4′); IR(KBr): ν (cm⁻¹); 3350 (NH₂); 1680 and 1625 (C═O).

EXAMPLE 352-(5-Acetamidofuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole

In a three-necked bottle, to 0.300 g (1.01 mmol, 1 eq) of2-(5-aminofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho-[2,3-d]-thiazole,one adds, dropwise and at ambient temperature, 200 μL (2.02 mmol; 2 eq)of acetic anhydride, then 60 μL (1.01 mmol; 1 eq) of acetic acid. Thesuspension obtained is heated at 50° C., and becomes bordeaux red. After2 h of reaction, the suspension is cooled and dissolved in 500 mL ofdichloromethane. The solution is washed two times with a saturatedsolution of sodium hydrogen carbonate, then several times with wateruntil the aqueous has a neutral pH. After drying the organic phase overcalcium chloride and evaporation of the solvents, 0.330 g of solid rawproduct (bordeaux red) is obtained. This solid is purified on a flashcolumn (support: silica 6-35 μm, eluant: dichloromethane/methanol,98/2). The compound obtained is dissolved in dichloromethane, thenfiltered through micropores. The filtrate is concentrated and theprecipitate formed is filtered through fritted [glass] to produce 0.145g of2-(5-acetamidofuran-2-yl)-4,9-dihydro-4,9-dioxo-naphtho[2,3-d]thiazolein the form of brick-red crystals.

Yield: 42%; Melting point: >260° C.; Rf: 0.34 (Dichloromethane/Methanol,95/5); MS (APcI+): m/z 339 (M⁺H⁺); ¹H-NMR (DMSO-d₆): δ (ppm); 11.75 (s,1H, NH); 8.28 (m, 1H, H-5 or H-8); 8.23 (m, 1H, H-5 or H-8); 8.03 (m,2H, H-6, H-7); 7.69 (d, 1H, H-3′, J_(H3′-H4′)=3.73 Hz); 6.62 (d, 1H,H-4′, J_(H3′-H4′)=3.74 Hz); 2.22 (s, 3H, CH₃); ¹³C-NMR (DMSO-d₆): δ(ppm) 177.9, 176.5 (2C, C-4, C-9); 167.5 (1C, C-5′); 155.2 (1C, C-2);139.0 (1C, C-2′); 134.6, 134.4 (2C, C-6, C-7); 132.7, 132.6 (2C, C-4a,C-8a); 127.2, 126.4 (2C, C-5, C-8); 118.1 (1C, C-3′); 97.0 (1C, C-4′);23.4 (1C, CH₃); IR (Kbr): (cm¹); 3033 (N−H); 1682 and 1655 (C═O).

EXAMPLE 364,9-Dihydro-4,9-dioxo-2-(5-hydroxymethylfuran-2-yl)naphtho[2,3-d]thiazole

17.36 g (72.2 mmol, 5 eq) of nonahydrated sodium sulfide are dissolvedin 70 mL of water. The solution is heated at 60° C., then 3.00 g (14.4mmol, 1 eq) of 2-amino-3-chloro-1,4-dihydro-1,4-dioxo-naphthalene areadded. After 30 min of stirring at 60° C., the solution is cooled toambient temperature. To the reaction medium, which has turned blue, 2.43g (14.5 mmol, 1 eq) of 5-acetoxymethyl-2-furaldehyde are added; after 5min, 3 mL of acetic acid are then added dropwise. The medium turnschestnut brown-orangish; the precipitate formed is filtered throughfritted glass, washed with water, and dried to produce 3.30 g of rawproduct which are purified on a flash column (support: silica 6-35 μm; 5cm φ, 15 cm h, eluant: CH₂Cl₂/MeOH, 96/4). The orange product obtainedis recrystallized in dimethylformamide, uncolored on animal black, andfiltered through Celite and micropores to produce 0.80 g of4,9-dihydro-4,9-dioxo-2-(5-hydroxymethylfuran-2-yl)naphtho[2,3-d]thiazolein the form of ocher crystals.

Yield: 17%; Melting point: >260° C.; Rf: 0.60 (CH₂Cl₂/MeOH, 96/4); MS(I.E): m/z 311 (M⁺); ¹H-NMR (DMSO-d₆): δ (ppm); 8.20 (m, 1H, H-5 orH-8); 8.11 (m, 1H, H-5 or H-8); 7.91 (m, 2H, H-6, H-7); 7.46 (d, 1H,H-3′, J_(H3′-H4′)=3.1 Hz); 6.65 (d, 1H, H-4′, J_(H3′-H4′)=3.1 Hz); 5.55(t, 1H, OH, J_(OH-CH2)=5.6 Hz); 4.54 (d, 2H, CH₂, J_(CH2-OH)=5.6 Hz);¹³C-NMR (DMSO-d₆): δ (ppm); 177.6, 176.6 (2C, C-4, C-9); 160.0 (1C,C-5′); 158.4 (1C, C-2); 146.6 (1C, C-2′); 134.4 (2C, C-6, C-7); 132.3,132.1 (2C, C-4a, C-8a); 127.0, 126.2 (2C, C-5, C-8); 127.0, 126.2 (2C,C-5, C-8); 114.9 (1C, C-3′); 110.5 (1C, C-4′); 55.6 (1C, CH₂); IR (Kbr):ν (cm⁻¹); 3374 (OH), 1677 and 1656 (C═O).

EXAMPLE 372-(5-Acetoxymethylfuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole

To 5.00 g (24 mmol) of2-amino-3-mercapto-1,4-dihydro-1,4-dioxonaphthalene, 40 mL ofN-methylpyrrolidone are added at 0° C. under an argon atmosphere. Thereaction mixture is stirred for 10 min, then 4.10 g (24 mmol) of5-acetoxymethyl-2-furaldehyde are added at 0° C. After 5 h of stirringat this temperature, the mixture is allowed to return to ambienttemperature. The content of the three-necked flask is poured into 250 mLof water, and the chestnut brown precipitate formed is dissolved inethyl acetate. The organic phase is extracted, dried over magnesiumsulfate, filtered, and evaporated at reduced pressure.

The chestnut brown solid obtained is purified a first time in a column(support: silica 6-35 μm; eluant: CH₂Cl₂/MeOH/AcOEt, 97/1/2) to produce3.29 g of product.

A sample of 0.500 g is collected, then purified a second time bypreparative plates (support: silica; eluant: CH₂Cl₂/MeOH/AcOEt, 97/1/2),to produce 0.107 mg of2-(5-acetoxymethylfuran-2-yl)-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazolein the form of yellow crystals.

Yield: 38%; Melting point: 204° C.; Rf: 0.52 (heptane/AcOEt, 50/50); MS(I.E.): m/z 353(M⁺); ¹H-NMR (CDCl₃): δ (ppm); 8.34 (m, 1H, H-5 or H-8);8.24 (m, 1H, H-5 or H-8); 7.81 (m, 2H, H-6, H-7); 7.41 (d, 1H, H-3′,J_(H3′-H4′)32 3.74 Hz); 6.64 (d, 1H, H-4′, J_(H4′-H3′)=3.32 Hz); 5.15(s, 2H, CH₂); 2.14 (s, 3H, CH₃); ¹³C-NMR (CDCl₃): δ (ppm); 134.39,134.14 (2C, C-6, C-7); 133.30, 132.83 (2C, C-4a, C-8a); 127.86, 126.94(2C, C-5, C-8); 114.52, 113.77 (2C, C-3′, C-4′); 57.67 (1C, CH₂); 20.83(1C, CH₃); IR (KBr): ν (cm⁻¹); 1734, 1686 and 1669 (C═O).

EXAMPLE 384,9-Dihydro-4,9-dioxo-2-(5-methyl-2-furyl)naphtho-[2,3-d]thiazole

To a buffer solution at pH 11 (containing 6.2 g of H₃BO₃ and 4 g of NaOHper liter), 4.6 g (19.3 mmol) of nonahydrated sodium sulfide are added.The mixture is stirred at 15° C. under an argon atmosphere until thedissolution is complete, then 2 g (9.6 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene are added. After 20min, 0.96 mL (9.6 mmol) of 5-methyl-2-furfural is added to the reactionmedium, which has turned blue.

After 4 h of stirring, the content of the three-necked flask is pouredinto 100 mL of ethyl acetate and the three-necked flask is rinsed with50 mL of water. The organic phase is washed three times with 80 mL ofwater and dried over magnesium sulfate. After evaporation of the solventat reduced pressure, 1 g of orange product is formed, which is purifiedover a cake (support: silica 6-35 μm; eluant: CH₂Cl₂/heptane: 50/50,90/10, and 100) to produce 0.560 g of orangish crystals, which arerecrystallized in an AcOEt/CH₂Cl₂ mixture: 70/30 after color removalwith animal charcoal.

Yield: 35%; Melting point: 254° C.; Rf: 0.48 (CH₂Cl₂); MS (I.E): m/z 295(M⁺)^(·); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.22 (dd, 1H, H-5 or H-8, J_(H5-H6)or J_(H7-H8)=8.85 Hz, J_(H5-H7) or J_(H6-H8)=1.73 Hz); 8.16 (m, 1H, H-5or H-8); 7.80 (m, 2H, H-6, H-7); 7.28 (d, 1H, H-3′, J_(H3′-H4′)=3.35Hz); 6.29 (d, 1H, H-4′, J_(H3′-H4′)=3.35 Hz); 2.44 (s, 3H, CH₃); ¹³C-NMR(CDCl₃): δ (ppm); 178.43, 178.12 (C-4, C-9); 164.07 (C-2); 157.79(C-5′); 155.00 (C-3a); 146.92 (C-2′); 140.60 (C-9a); 134.54, 134.32(C-6, C-7); 133.50, 133.04 (C-4a, C-8a); 127.72, 126.94 (C-5, C-8);115.43, 110.16 (C-3′, C-4′); 14.09 (CH₃); IR (KBr): ν (cm⁻¹); 1684 and1653 (C═O).

EXAMPLE 394,9-Dihydro-2-(4,5-dimethyl-2-furyl)4,9-dioxonaphtho-[2,3-d]thiazole

To 200 mL of a solution of sodium hydroxide (pH=10.66), 6.94 g (28.9mmol) of nonahydrated sodium sulfide are added. The mixture is stirredat 15° C. under an argon atmosphere until the dissolution is complete,then 3.00 g (14.4 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene are added. After 3 hof stirring at ambient temperature, 1.80 g (14.4 mmol) of4,5-dimethyl-2-furaldehyde are added to the reaction medium, which hasturned blue; after 5 min, 5 mL of acetic acid are added dropwise, andthe medium turns orangish.

The stirring is continued for 5 min, then the argon bubbling is replacedwith compressed air for 3 min.

The black precipitate formed is filtered through fritted glass, washedwith water, and dried to produce 4.00 g of product, which are purifiedin a flash column (support: silica 6-35 μm; eluant: heptane/AcOEt:85/15).

The orange product obtained after evaporation of the solvent isuncolored with animal charcoal, then recrystallized in ethyl acetate toproduce 2.50 g of4,9-dihydro-2-(4,5-dimethyl-2-furyl)4,9-dioxonaphtho[2,3-d]-thiazole inthe form of orange crystals.

Yield: 90%; Melting point: 250° C.; Rf: 0.2 (CH₂Cl₂); MS (I.E): m/z 309(M⁺); ¹H-NMR (CDCl₃): δ (ppm); 8.31 (dd, 1H, H-5 or H-8, J_(H5-H6) orJ_(H5-H7)=8.85 Hz, J_(H5-H7) or J_(H6-H8)=1.73 Hz); 8.22 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H5-H7)=8.85 Hz, J_(H5-H7) or J_(H6-H8)=1.73 Hz);7.80 (m, 2H, H-6, H-7); 7.23 (s, 1H, H-3′); 2.35 (s, 3H, CH₃ at 5′);2.17 (s, 3H, CH₃ at 4′); ¹³-NMR (CDCl₃): δ (ppm); 178.43, 178.12 (2C,C-4, C-9); 172 (C-2); 164.21 (C-2′); 155.35 (C-3a); 153.18 (C-5′);145.32 (C-9a); 134.13, 133.97 (2C, C-6, C-7); 133.24, 132.89 (2C, C-4a,C-8a); 127.72, 126.79 (2C, C-5, C-8); 118.78 (C-4′); 117.51 (C-3′);12.50 (CH₃ at 5′); 10.00 (CH₃ at 4′); IR (KBr): ν (cm⁻¹); 1682 and 1656(C═O).

EXAMPLE 404,9-Dihydro-4,9-dioxo-2-(5-phenyl-2-oxazolyl)naphtho[2,3-d]thiazole

To 2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene (0.21 g, 1.0 mmol)in distilled water (7 mL), nonahydrated sodium sulfide (0.98 g, 4.1mmol) is added under an argon atmosphere. The mixture is heated toreflux under an argon atmosphere until the coloration of the reactionmedium has become completely blue. 5-phenyl-2-oxazole carbaldehyde [sic;carboxyaldehyde] (CAS No. 96829-89-9) (0.21 g, 1.4 mmol) in solution intetrahydrofuran (6 mL) is then added as well as acetic acid (0.25 mL).The reaction medium is then stirred under an argon atmosphere at ambienttemperature for 1 h. An orange precipitate then forms. The precipitateis then filtered and washed with water. The orange precipitate (0.28 g)is then partially dissolved in diethyl ether (21 mL). After filtrationof the insoluble content, the filtrate is concentrated at reducedpressure and chromatographed using a flash column (support: silica 6-35μm; eluant: dichloromethane/methanol: 98/2). The orange product obtainedafter evaporation is uncolored with animal charcoal, then filteredthrough micropores. Orange crystals (0.17 g) of4,9-dihydro-4,9-dioxo-2-(5-phenyl-2-oxazolyl)naphtho[2,3-d]thiazole arethus obtained after evaporation.

Yield: 79%; Melting point: >260° C.; Rf: 0.64 (acetonitrile in reversephase); 0.76 (dichloromethane/methanol, 98/2); MS (I.E): m/z 358(M⁺)^(·), 330 (M⁺−CO); ¹H-NMR (CDCl₃): δ (ppm); 8.36 (m, 1H, H-5 orH-8); 8.26 (m, 1H, H-5 or H-8); 7.85 (m, 4H, H-6, H-7, H-2″, H-6″); 7.60(d, 1H, H-4′, J=0.9 Hz); 7.55-7.35 (m, 2H, H-3″, H-5″); 7.27 (d, 1H,H-4″, J=0.9 Hz); ¹³C-NMR (CDCl₃): δ (ppm); 178.23, 177.36 (2C, C-4 andC-9); 160.34 (1C, C-2); 155.20 (1C, C-2′); 154.60 (1C, C-3a); 154.37(1C, C-5′); 142.98 (1C, C-9a); 134.71, 134.27 (2C, C-6 and C-7); 133.04,132.77 (2C, C-4a and C-8a); 129.92 (1C, C-8 or C-5); 129.15 (2C, C-2″and C-6″); 128.02 (1C, C-5 or C-8); 127.16 (1C, C-4′); 126.51 (1C,C-1″); 125.22 (2C, C-3″ and C-5″); 124.66 (1C, C-4″); IR (KBr): ν cm⁻¹;1681 and 1654 (C═O), 1589 (N═C—O).

EXAMPLE 41 4,9-Dihydro-4,9-dioxo-2-(2-thiazolyl)naphtho[2,3-d]-thiazole

To 1.12 g (5.39 mmol) of2-amino-3-chloro-1,4-dihydro-1,4-dioxonaphthalene in 38 mL of water,5.18 g (21.56 mmol) of nonahydrated sodium sulfide are added. Themixture is heated to reflux until the coloration of the reaction mediumhas turned completely blue. 0.73 g (6.46 mmol) of 2-thiazolecarboxyaldehyde, then 1.3 mL (22.75 mmol) of acetic acid, are added at90° C. The reaction medium is then immediately cooled to 0° C. using anice bath. A precipitate then forms. The reaction medium is stirred for 1h at 0° C. The precipitate is then filtered and washed with water. Theprecipitate is then partially dissolved in dichloromethane. During thefiltration and the solubilization in dichloromethane, a change in coloroccurs: the chestnut brown precipitate takes on a yellow-brown color.After filtration of the insoluble content and evaporation of thesolvent, 0.3 g of4,9-dihydro-4,9-dioxo-2-(2-thiazolyl)naphtho[2,3-d]thiazole are obtainedin the form of yellow-brown crystals.

Yield: 19%; Melting point: >260° C.; Rf: 0.22 (dichloromethane); MS(APcI−): m/z 298 (M⁻); ¹H-NMR (CDCl₃): δ (ppm); 8.36 (m, 1H, H-5 orH-8); 8.26 (m, 1H, H-8 or H-5); 8.03 (d, 1H, H-4′, J_(H4′-H5′)=3.06 Hz);7.84 (m, 2H, H-6, H-7); 7.67 (d, 1H, H-5′, J_(H4′-H5′)=3.05 Hz); ¹³C-NMR(CDCl₃): δ (ppm); 145.18 (1C, C-4′); 134.91, 134.53 (2C, C-6, C-7);128.24, 127.41 (2C, C-8, C-5); 124.59 (1C, C-5′); IR (KBr): ν (cm⁻¹);1675, 1652 (C═O).

EXAMPLES 42 AND 434,9-Dihydro-4,9-dioxo-6-fluoro-2-(2-furyl)-naphtho[2,3-d]thiazole and4,9-Dihydro-4,9-dioxo-7-fluoro-2-(2-furyl)-naphtho-[2,3-d]thiazole

Synthesis Intermediates:

2,3-Dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene

To a solution of 1,4-dihydro-1,4-dioxo-6-fluoronaphthalene (CAS No.148541-61-1) (12.5 g, 71 mmol) in chloroform (250 mL), 36 mL (710 mmol)of bromine are added. The solution is heated to reflux for 12 h, thenallowed to return to ambient temperature. After bubbling compressed airthrough it, the solution is concentrated at reduced pressure and thesolid obtained is washed 5 times with heptane; 15.0 g of a beige powderof 2,3-dibromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene are produced.

Yield: 65%; Melting point: 158° C.; Rf: 0.80 (dichloromethane); MS(APcI−): m/z 332, 334, 336 (M⁻); ¹H-NMR (CDCl₃): δ (ppm); 8.22 (dd, 1H,H-8, J_(H7-H8)=8.55 Hz, J_(H-F)=5.19 Hz); 7.81 (dd, 1H, H-5,J_(H-F)=8.55 Hz, J_(H5-H7)=2.75 Hz); 7.45 (td, 1H, H-7,J_(H-F)=J_(H7-H8)=8.55 Hz, J_(H5-H7)=2.75 Hz); IR (KBr): ν (cm⁻¹); 1680(C═O).

2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene and

2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-7-fluoronaphthalene

In a solution of 6-fluoro-2,3-dibromo-1,4-dihydro-1,4-dioxonaphthalene(10.00 g, 30 mmol) in tetrahydrofuran (500 mL), ammonia is bubbled in atambient temperature for 2 h, then compressed air is passed through thesolution for 15 min. After evaporation of the solvent at reducedpressure, the solid obtained is first cleaned over silica gel cake(support: silica 6-35 μm; 5 cm φ; h=15 cm; eluant:dichloromethane/heptane, 90/10) purified by three flash chromatographieson a silica gel column (support: silica 6-35 μm; 5 cm φ; 30 cm h;eluant: dichloromethane/heptane, 90/10). 4.78 g of a red powder, amixture of 2-amino-3-bromo-6-fluoro-1,4-dihydro-1,4-dioxonaphthalene and2-amino-3-bromo-7-fluoro-1,4-dihydro-1,4-dioxonaphthalene, are produced.

Yield: 60% (isomer ratio: 75/25); Melting point: 190-195° C.; Rf: 0.40(dichloromethane); MS (APcI−): m/z 270 (M⁻); ¹H-NMR (acetone-d₆): δ(ppm); 8.27 (dd, 1H, H-5 or H-8, J_(H5-H6) or J_(H7-H8)=8.54 Hz,J_(H-F)5.18 Hz); 7.85 (dd, 1H, H-5 or H-8, J_(H-F)=8.54 Hz, J_(H5-H7) orJ_(H6-H8)=2.74 Hz); 7.71 (td, 1H, H-6 or H-7 minority isomer,J_(H-F)=J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H5-H7) or J_(H6-H8)=2.74 Hz);7.64 (td, 1H, H-6 or H-7 majority isomer, J_(H-F)=J_(H5-H6) orJ_(H7-H8)=8.54 Hz, J_(H5-H7) or J_(H6-H8)=2.74 Hz); IR (KBr): ν (cm⁻¹);3357 (NH₂), 1685 (C═O).

4,9-Dihydro-4,9-dioxo-6-fluoro-2-(2-furyl)naphtho-[2,3-d]thiazole and

4,9-Dihydro-4,9-dioxo-7-fluoro-2-(2-furyl)naphtho-[2,3-d]thiazole

To 0.50 g (1.8 mmol; 1.0 eq) of a 75/25 mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene and2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-fluoronaphthalene, 25 mL of asodium hydroxide solution (5×10⁻⁴M) containing 1.11 g (4.6 mmol; 2.5 eq)of nonahydrated sodium sulfide are added. The red suspension is heatedfor 30 min at 80° C. until a dark blue solution is obtained; 0.3 mL (3.6mmol; 2.0 eq) of 2-furaldehyde is then added. After 90 min of heating at80° C., the dark red solution obtained is allowed to return to ambienttemperature. A few drops of glacial acetic acid are then added, then theorange precipitate formed is filtered, washed three times with water,and dried; 0.5 g of a mixture of two isomers of4,9-dihydro-4,9-dioxo-6-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole and4,9-dihydro-4,9-dioxo-7-fluoro-2-(2-furyl)naphtho[2,3-d]-thiazole in theform of red crystals is obtained.

The isomers are separated by flash chromatography on a silica gel column(silica 6-35 μm; 4.5 cm φ; 30 cm h; eluant: dichloromethane), then bypreparative HPLC (column: Dynamax 60-A Si 83-141C; eluant: heptane/ethylacetate: 80/20) to produce 0.125 g of the less polar product and 0.375 gof the more polar product.

Yield: 90% (isomer ratio: 75/25).

The Less Polar Product

Melting point: >265° C.; Rf: 0.32 (heptane/ethyl acetate, 80/20); MS(APcI−): m/z 299 (M⁻); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.17 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=8.55 Hz, J_(H-F)=5.50 Hz); 7.85 (dd, 1H, H-5or H-8, J_(H-F)=8.55 Hz, J_(H5-H7) or J_(H6-H8)=2.44 Hz); 7.61 (m, 1H,H-5′); 7.13 (td, 1H, H-6 or H-7, J_(H5-H6) or J_(H7-H8)=J_(H-F)=8.55 Hz,J_(H5-H7) or J_(H6-H8)=2.44 Hz); 7.33 (d, 1H, H-3′, J_(H3′-H4′)=3.66Hz); 6.61 (dd, 1H, H-4′, J_(H3′-H4′)=3.66 Hz, J_(H4′-H5′)=1.83 Hz); IR(KBr): ν (cm⁻¹); 1680 and 1655 (C═O).

The More Polar Product

Melting point: >265° C.; Rf: 0.25 (heptane/diethyl acetate, 80/20); MS(APcI−): m/z 299 (M⁻); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.23 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H-F)=5.50 Hz); 7.78 (dd, 1H, H-5or H-8, J_(H-F)=8.54 Hz, J_(H5-H7) or J_(H6-H8)=2.75 Hz); 7.61 (m, 1H,H-5′); 7.40 (td, 1H, H-6 or H-7, J_(H5-H6) or J_(H7-H8)=J_(H-F)=8.55 Hz,J_(H5-H7) or J_(H6-H8)=2.75 Hz); 7.33 (d, 1H, H-3′, J_(H3′-H4′)=3.66Hz); 6.60 (dd, 1H, H-4′, J_(H3′-H4′)=3.66 Hz, J_(H4′-H5′)=1.83 Hz); IR(KBr): ν (cm⁻¹); 1680 and 1660 (C═O).

EXAMPLES 44 AND 454,9-Dihydro-4,9-dioxo-6-fluoro-2-phenylnaphtho[2,3-d]thiazole and4,9-Dihydro-4,9-dioxo-7-fluoro-2-phenylnaphtho[2,3-d]thiazole

To 0.80 g (2.96 mmol; 1.0 eq) of a 75/25 mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene and2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-fluoronaphthalene, 40 mL of anaqueous solution of nonahydrated sodium sulfide are added (1.78 g; 7.40mmol; 2.5 eq). The red suspension is heated for 0.5 h at 80° C. until adark blue solution is obtained; 0.6 mL (5.90 mmol; 2.0 eq) ofbenzaldehyde is then added, and the solution is stirred for anadditional 2 h at 80° C. The chestnut brown solution obtained is allowedto return to ambient temperature, then a few drops of glacial aceticacid are added. The dark green precipitate formed is filtered, washedthree times with water, and dried; 0.820 g of a mixture of4,9-dihydro-4,9-dioxo-6-fluoro-2-phenylnaphtho-[2,3-d]thiazole and4,9-dihydro-4,9-dioxo-7-fluoro-2-phenylnaphtho[2,3-d]thiazole in theform of yellow crystals is obtained.

The isomers are separated by three successive flash chromatographies ona silica gel column (support: silica 6-35 μm; 9.5 cm φ; 25 cm h; eluant:dichloromethane/heptane, 70/30) to produce a 0.205 g of the less polarproduct and 0.615 g of the more polar product.

Yield: 89% (isomer yield: 75/25);

Less Polar Product

Melting point: 261° C.; Rf: 0.48 (dichloromethane/heptane: 80/20); MS(APcI−): m/z 309 (M⁻); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.20 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H-F)=5.18 Hz); 8.09 (m, 2H, H-2′and H-6′); 7.90 (dd, 1H, H-5 or H-8, J_(H-F)=8.54 Hz, J_(H5-H7) orJ_(H6-H8)=2.74 Hz); 7.50 (m, 4H, H-6 or H-7, H-3′, H-4′ and H-5′); IR(KBr): ν (cm⁻¹); 1680 and 1660 (C═O).

The More Polar Product

Melting point: 241° C.; Rf: 0.41 (dichloromethane/heptane: 80/20); MS(APcI−): m/z 309 (M⁻); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.28 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H-F)=5.19 Hz); 8.08 (dd, 2H,H-2′ and H-6′, J_(H2′-H3′)=J_(H5′-H6′)=8.05 Hz,J_(H4′-H6′)=J_(H2′-H4′)=1.65 Hz); 7.81 (dd, 1H, H-5 or H-8, J_(H-F)=8.54Hz, J_(H5-H7) or J_(H6-H8)=2.44 Hz); 7.50 (m, 4H, H-6 or H-7, H-3′ andH-4′ and H-5′); IR (KBr): ν (cm⁻¹); 1680 and 1660 (C═O).

EXAMPLES 46 AND 474,9-Dihydro-4,9-dioxo-6-fluoro-2-(5-methyl-2-furyl)naphtho[2,3-d]thiazoleand4,9-Dihydro-4,9-dioxo-7-fluoro-2-(5-methyl-2-furyl)naphtho[2,3-d]thiazole

To 0.80 g (2.96 mmol; 1.0 eq) of a 75/25 mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene and2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-fluoronaphthalene, 40 mL of anaqueous solution of nonahydrated sodium sulfide (1.78 g; 7.40 mmol; 2.5eq) are added. The red suspension is heated for 30 min at 80° C. until adark blue solution is obtained; 0.59 mL (5.90 mmol; 2.0 eq) of5-methyl-2-furaldehyde are then added, and the solution is stirred foran additional 90 min at 80° C. The dark brown solution obtained isallowed to return to ambient temperature, then a few drops of glacialacetic acid are added. The greenish precipitate formed is filtered,washed three times with water, and dried; 0.705 g of a mixture of4,9-dihydro-4,9-dioxo-6-fluoro-2-(5-methyl-2-furyl)naphtho[2,3-d]thiazoleand4,9-dihydro-4,9-dioxo-7-fluoro-2-(5-methyl-2-furyl)naphtho-[2,3-d]thiazolein the form of dark red crystals is obtained.

The isomers are separated by three successive flash chromatographies ona silica gel column (support: silica 6-35 μm; 5 cm φ; 35 cm h; eluant:dichloromethane/heptane, 90/10) to produce 0.177 g of the less polarproduct and 0.528 g of the more polar product.

Yield: 76% (isomer ratio: 75/25);

The Less Polar Product

Melting point: 260° C.; Rf: 0.40 (dichloromethane/heptane: 80/20); MS(APcI−): m/z 313 (M⁻); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.18 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H-F)=5.18 Hz); 7.86 (dd, 1H, H-5or H-8, J_(H-F)=8.54 Hz, J_(H5-H7) or J_(H6-H8)=2.75 Hz); 7.41 (td, 1H,H-6 or H-7, J_(H-F)=J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H5-H7) orJ_(H6-H8)=2.75 Hz); 7.25 (d, 1H, H-3′, J_(H3′-H4′)=3.36 Hz); 6.24 (d,1H, H-4′, J_(H3′-H4′)=3.36 Hz); 2.39 (s, 3H, CH₃); IR (KBr): ν (cm⁻¹);1685 and 1650 (C═O).

The More Polar Product

Melting point: 238° C.; Rf: 0.30 (dichloromethane/heptane, 80/20); MS(APcI−): m/z 313 (M⁻); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.25 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H-F)=5.18 Hz); 7.80 (dd, 1H, H-5or H-8, J_(H-F)=8.54 Hz, J_(H5-H7) or J_(H6-H8)=2.75 Hz); 7.42 (td, 1H,H-6 or H-7, J_(H5-H6) or J_(H7-H8)=J_(H-F)=8.54 Hz, J_(H5-H7) orJ_(H6-H8)=2.75 Hz); 7.25 (d, 1H, H-3′, J_(H3′-H4′)=3.36 Hz); 6.24 (d,1H, H-4′, J_(H3′-H4′)=3.36 Hz); 2.39 (s, 3H, CH₃); IR (KBr): ν (cm⁻¹);1675 and 1655 (C═O).

EXAMPLES 48 AND 494,9-Dihydro-4,9-dioxo-6-fluoro-2-(4-fluorophenyl)naphtho[2,3-d]thiazoleand4,9-Dihydro-4,9-dioxo-7-fluoro-2-(4-fluorophenyl)naphtho[2,3-d]thiazole

To 0.80 g (2.96 mmol; 1.0) eq) of a 75/25 mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene and2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-fluoronaphthalene, 40 mL of anaqueous solution of nonahydrated sodium sulfide (1.78 g; 7.40 mmol; 2.5eq) are added. The red suspension is heated for 30 min at 80° C. until adark blue solution is obtained; 0.63 mL (5.80 mmol; 2.0 eq) of4-fluorobenzaldehyde is then added, and the solution is stirred for anadditional 90 min at 80° C. The dark brown solution obtained is allowedto return to ambient temperature, then a few drops of glacial aceticacid are added. The greenish precipitate formed is filtered, washedthree times with water, and dried; 0.570 g of a mixture of4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-fluorophenyl)naphtho[2,3-d]thiazoleand4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-fluorophenyl)naphtho[2,3-d]thiazolein the form of bright yellow crystals is obtained.

The isomers are separated by three successive flash chromatographies ona silica gel column (support: silica 6-35 μm; 5.5 cm φ; 40 cm h; eluant:dichloromethane/heptane, 80/20), and then each fraction is washedseveral times with heptane to produce 0.143 g of the less polar productand 0.427 g of the more polar product.

Yield: 59% (isomer ratio: 75/25).

Less Polar Product

Melting point: >265° C.; Rf: 0.42 (dichloromethane/heptane, 80/20); MS(APcI−): m/z 327 (M⁻); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.21 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H-F)=5.19 Hz); 8.10 (dd, 2H,H-2′ and H-6′, J_(H2′-H3′)=J_(H5′-H6′)=8.85 Hz, J_(H2′-F)=J_(H6-F)=5.19Hz); 7.89 (dd, 1H, H-5 or H-8, J_(H-F)=8.54 Hz, J_(H5-H7) orJ_(H6-H8)=2.75 Hz); (td, 1H, H-6 or H-7, J_(H-F)=J_(H5-H6) orJ_(H7-H8)=8.54 Hz, J_(H5-H7) or J_(H6-H8)=2.75 Hz); 7.20 (t, 2H, H-3′and H-5′, J_(H-F)=J_(H2′-H3′)=J_(H5′-H6′)=8.85 Hz); IR (KBr): ν (cm⁻¹);1675 and 1655 (C═O).

The More Polar Product

Melting point: >265° C.; Rf: 0.40 (dichloromethane/heptane, 80/20); MS(APcI−): m/z 327 (M⁻); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.28 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H-F)=5.19 Hz); 8.11 (dd, 2H,H-2′ and H-6′, J_(H2′-H3′)=J_(H5′-H6′)=8.85 Hz, J_(H2′-F)=J_(H6′-F)=5.19Hz); 7.81 (dd, 1H, H-5 or H-8, J_(H-F)=8.54 Hz, J_(H5-H7) orJ_(H6-H8)=2.75 Hz); 7.45 (td, 1H, H-6 or H-7, J_(H-F)=J_(H5-H6) orJ_(H7-H8)=8.54 Hz, J_(H5-H7) or J_(H6-H8)=2.75 Hz); 7.20 (t, 2H, H-3′and H-5′, J_(H-F)=J_(H2′-H3′)=J_(H5′-H6′)=8.85 Hz); IR (KBr): ν (cm⁻¹);1675 and 1660 (C═O).

EXAMPLES 50 AND 514,9-Dihydro-4,9-dioxo-6-fluoro-2-(4-methylphenyl)naphtho[2,3-d]thiazoleand4,9-Dihydro-4,9-dioxo-7-fluoro-2-(4-methylphenyl)naphtho[2,3-d]thiazole

To 1 g (3.70 mmol; 1.0 eq) of a 75/25 mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-fluoronaphthalene and2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-fluoronaphthalene, 50 mL of anaqueous solution of nonahydrated sodium sulfide (2.22 g; 9.20 mmol; 2.5eq) are added. The red suspension is heated for 30 min at 80° C. until adark blue solution is obtained; 0.87 mL (7.40 mmol; 2.0 eq) of4-methylbenzaldehyde is then added, and the solution is stirred for anadditional 90 min at 80° C. The dark brown solution obtained is allowedto return to ambient temperature, then a few drops of glacial aceticacid are added. The greenish precipitate that forms is filtered, washedthree times with water, and dried; 0.623 g of a mixture of4,9-dihydro-4,9-dioxo-6-fluoro-2-(4-methylphenyl)naphtho[2,3-d]thiazoleand4,9-dihydro-4,9-dioxo-7-fluoro-2-(4-methylphenyl)naphtho[2,3-d]thiazoleis added in the form of yellow crystals.

The isomers are separated by flash chromatography on a silica gel column(support: silica 6-35 μm; 9 cm φ; 35 cm h; eluant:dichloromethane/heptane, 70/30). The combined fractions are concentratedat reduced pressure, and the solid product formed is washed over frittedglass two times with a minimum amount of methanal and five times withheptane to produce 0.467 g of the more polar product and 0.156 g of theless polar product in the form of yellow crystals.

Yield: 52% (isomer ratio: 75/25).

The More Polar Product

Melting point: >260° C.; Rf: 0.42 (dichloromethane/heptane: 70/30); MS(APcI−): m/z 323 (M⁻); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.27 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H-F)=5.19 Hz); 7.96 (d, 2H, H-2′and H-6′, J_(H2′-H3′)=J_(H5′-H6′)=8.24 Hz); 7.80 (dd, 1H, H-5 or H-8,J_(H-F)=8.54 Hz, J_(H5-H7) or J_(H6-H8)=2.75 Hz); 7.44 (td, 1H, H-6 orH-7, J_(H-F)=J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H5-H7) or J_(H6-H8)=2.75Hz); 7.30 (d, 2H, H-3′ and H-5′, J_(H2′-H3′)=J_(H5′-H6′)=8.24 Hz); 2.38(s, 3H, CH₃); IR (KBr) ν (cm⁻¹); 1670 and 1665 (C═O).

The More Polar Product

Melting point: >260° C.; Rf: 0.46 (dichloromethane/heptane: 70/30); MS(APcI−): m/z 323 (M⁻); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.20 (dd, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H-F)=5.19 Hz); 7.97 (d, 2H, H-2′and H-6′, J_(H2′-H3′)=J_(H5′-H6′)=8.24 Hz); 7.88 (dd, 1H, H-5 or H-8,J_(H-F)=8.85 Hz, J_(H5-H7) or J_(H6-H8)=2.75 Hz); 7.42 (td, 1H, H-6 orH-7, J_(H-F)=J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H5-H7) or J_(H6-H8)=2.75Hz); 7.31 (d, 2H, H-3′ and H-5′, J_(H2′-H3′)=J_(H5′-H6′)=8.24 Hz); 2.39(s, 3H, CH₃); IR (KBr) ν (cm⁻¹); 1675 and 1655 (C═O).

EXAMPLES 52 AND 534,9-Dihydro-4,9-dioxo-5-fluoro-2-(2-furyl)naphtho-[2,3-d]thiazole4,9-Dihydro-4,9-dioxo-8-fluoro-2-(2-furyl)naphtho-[2,3-d]thiazole

Synthesis Intermediates:

2,3-Dibromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene

To a solution of 1,4-dihydro-1,4-dioxo-5-fluoronaphthalene (CAS No.62784-46-7) 2.45 g (71 mmol) in chloroform (60 mL), 7.34 mL (143 mmol)of bromine are added. The solution is heated to reflux for 12 h, thenallowed to return to ambient temperature. After bubbling in compressedair, the solution is concentrated at reduced pressure, and the solidbeige product obtained is purified on a flash column (support: silica;conditioning: heptane; eluant: CH₂Cl₂/heptane) to produce 3.44 g of2,3-dibromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene in the form ofbeige crystals.

Yield: 74%; Melting point: 100° C.; Rf: 0.63 (dichloromethane/heptane:80/20); MS (I.E.): m/z 333, 335, 337 (M⁺+1); ¹H-NMR (CDCl₃): δ (ppm);8.01 (d, 1H, H-8, J_(H7-H8)=7.94 Hz); 7.77 (m, 1H, H-7); 7.52 (m, 1H,H-6); IR (KBr): ν (cm⁻¹); 1704 (C═O).

2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene

2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-8-fluoronaphthalene

In a solution of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene(33 mg; 0.098 mmol) in tetrahydrofuran (5 mL), ammonia is bubbled in atambient temperature for 1 h, then compressed air is passed through thesolution for 15 min to eliminate the excess ammonia. After theevaporation of the solvent at reduced pressure, the solid red productobtained is purified on a preparative plate made of silica (eluant:CH₂Cl₂/heptane=90/10). 20.5 mg of a red powder, a mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene and2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-fluoronaphthalene, are obtained.

Yield: 77%; Melting point: 208° C.; Rf: 0.44 (dichloromethane); MS(APcI−): m/z 269, 271 (M⁻); ¹H-NMR (CDCl₃): δ (ppm); 7.98 (d, 1H, H-5 orH-8, J_(H5-H6) or J_(H7-H8)=7.63 Hz); 7.64 (m, 1H, H-6 or H-7); 7.31(dd, 1H, H-6 or H-7, J_(H5-H6) or J_(H7-H8)=J_(H-F)=8.55 Hz); 6.40-5.00(sl, 2H, NH₂); IR (KBr): ν (cm⁻¹); 3466, 3355 (NH₂), 1778, 1633 (C═O).

4,9-Dihydro-4,9-dioxo-5-fluoro-2-(2-furyl)naphtho-[2,3-d]thiazole

4,9-Dihydro-4,9-dioxo-8-fluoro-2-(2-furyl)naphtho-[2,3-d]thiazole

To 0.15 g (0.55 mmol; 1.0 eq) of a mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-fluoronaphthalene and2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-fluoronaphthalene in 25 mL ofwater, 0.33 g (1.38 mmol; 2.5 eq) of nonahydrated sodium sulfide isadded. The red suspension is heated for 30 min at 80° C. until a darkblue solution is obtained; 0.1 mL (1.1 mmol; 2.0 eq) of 2-furaldehyde isadded. After 90 min of heating at 80° C., the dark brown solutionobtained is allowed to return to ambient temperature. A few drops ofglacial acetic acid are added; then the chestnut brown precipitate formis filtered, washed three times with water, and dried. The mixture ofproducts obtained is purified by preparative thin-layer chromatography(silica 2 mm; eluant: dichloromethane/heptane/ethyl acetate, 80/10/10),then the two isomers of the expected compound are separated bypreparative thin-layer chromatography (silica 2 mm; eluant:dichloromethane) to produce 0.020 g of a mixture of4,9-dihydro-4,9-dioxo-5-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole and4,9-dihydro-4,9-dioxo-8-fluoro-2-(2-furyl)naphtho[2,3-d]thiazole in theform of orange crystals.

Yield: 12% (isomer ratio 47/53).

The Less Polar Isomer

Melting point: >260° C.; Rf: 0.34 (dichloromethane); MS (APcI+): m/z 300(M⁺H⁺); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.09 (dd, 1H, H-5 or H-8, J_(H5-H6) orJ_(H7-H8)=8.24 Hz, J_(H5-H7) or J_(H6-H8)=1.22 Hz); 7.75 (td, 1H, H-6 orH-7, J_(H5-H6) or J_(H7-H8)=J_(H6-H7)=7.94 Hz, J_(H-F)=4.58 Hz); 7.65(dd, 1H, H-5′, J_(H3′-H5′)=0.92 Hz, J_(H4′-H5′)=1.84 Hz); 7.46 (ddd, 1H,H-6 or H-7, J_(H-F)=10.98 Hz, J_(H6-H7)=8.24 Hz, J_(H5-H7) orJ_(H6-H8)=1.22 Hz); 7.35 (d, 1H, H-3′, J_(H3′-H4′)=3.67 Hz); 6.63 (dd,1H, H-4′, J_(H3′-H4′)=3.67 Hz, J_(H4′-H5′)=1.84 Hz); IR (KBr): ν (cm⁻¹);1680 and 1655 (C═O).

The More Polar Isomer

Melting point: >260° C.; Rf: 0.28 (dichloromethane); MS (APcI+): m/z 300(M⁺H ⁺); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.02 (dd, 1H, H-5 or H-8, J_(H5-H6)or J_(H7-H8)=7.63 Hz, J_(H5-H7) or J_(H6-H8)=1.22 Hz); 7.73 (td, 1H, H-6or H-7, J_(H5-H6) or J_(H7-H8)=J_(H6-H7)=8.24 Hz, J_(H-F)=4.58 Hz); 7.64(dd, 1H, H-5′, J_(H3′-H5′)=0.91 Hz, J_(H4′-H5′)=1.83 Hz); 7.46 (ddd, 1H,H-6 or H-7, J_(H-F)=11.29 Hz, J_(H5-H6) or J_(H7-H8)=8.54 Hz, J_(H5-H7)or J_(H6-H8)=1.22 Hz); 7.37 (d, 1H, H-3′, J_(H3′-H4′)=3.66 Hz); 6.64(dd, 1H, H-4′, J_(H3′-H4′)=3.66 Hz, J_(H4′-H5′)=1.83 Hz); IR (KBr): ν(cm⁻¹); 1680 and 1655 (C═O).

EXAMPLES 54 AND 556-Chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-naphtho-[2,3-d]thiazole7-Chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-naphtho-[2,3-d]thiazole

To 435 mg (1.79 mmol) of a mixture of2-amino-3,6-dichloro-1,4-dihydro-1,4-dioxonaphthalene and2-amino-3,7-dichloro-1,4-dihydro-1,4-dioxonaphthalene, one adds, atambient temperature and under argon, 1.72 g (7.16 mmol) of nonahydratedsodium sulfide in a solution in 15 mL of sodium carbonate, pH 10.6.After 30 min at 60° C. and under argon, 296 mL (3.58 mmol) of2-furaldehyde are added to the reaction medium, which has turnedcompletely blue. After 15 min of reflux, the argon introduction iseliminated, and the reaction mixture is diluted with 250 mL of water andextracted 3 times with 150 mL of dichloromethane. The organic phase isthen washed with 300 mL of water and evaporated to dryness to produce450 mg of the mixture of6-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-naphtho[2,3-d]thiazole and7-chloro-4,9-dihydro-4,9-dioxo-2-(2-furyl)-naphtho[2,3-d]thiazole in theform of orange crystals.

The two isomers are separated on silica cake (silica 40-60 mm, diameter7 cm, height 14 cm, eluant: dichloromethane/heptane, 90/10); 80 mg ofthe less polar product and 150 mg of the more polar product areobtained.

The Less Polar Product

Yield: 40% Melting point: >260° C. Rf: 0.42 (CH₂Cl₂/MeOH, 99/1); MS(APcI−): m/z 315 and 317 (M⁻); ¹H-NMR (CDCl₃): δ (ppm); 8.28 (d 1H, H-5or H-8, J_(H5-H-7) or J_(H6-H8)=2.08 Hz); 8.17 (d, 1H, H-5 or H-8,J_(H7-H8) or J_(H5-H6)=8.31 Hz); 7.75 (dd, 1H, H-6 or H-7, J_(H7-H8) orJ_(H5-H6)=8.31 Hz, J_(H5-H7) or J_(H6-H8)=2.07 Hz); 7.65 (m, 1H, H-5′);7.46 (d, 1H, H-3′, J_(H3′-H4′)=3.74 Hz); 6.66 (dd, 1H, H-4′,J_(H3′-H4′)=3.74 Hz, J_(H3′-H5′)=1.66 Hz); ¹³C-NMR (CDCl₃): δ (ppm);146.81 (C-5′); 134.72 (C-6 or C-7); 129.31, 128.53 (2C, C-5, C-8);114.75 and 114.11 (2C, C-3′, C-4′); IR (KBr): ν (cm⁻¹); 1675, 1665(C═O).

The More Polar Product

Yield: 26%; Melting point: >260° C.; Rf: 0.36 (CH₂Cl₂/MeOH, 99/1); MS(APcI+): m/z 316 and 318 (M⁺H⁺); ¹H-NMR (CDCl₃): δ (ppm); 8.28 (d 1H,H-5 or H-8, J_(H7-H8) or J_(H5-H6)=8 Hz); 8.18 (d, 1H, H-5 or H-8,J_(H5-H7) or J_(H6-H8)=1.84 Hz); 7.77 (dd, 1H, H-6 or H-7, J_(H7-H8) orJ_(H5-H6)=8.04 Hz, J_(H5-H7) or J_(H6-H8)=1.84 Hz); 7.67 (ls, 1H, H-5′);7.47 (d, 1H, H-3′, J_(H3′-H4′)=3.45 Hz); 6.66 (m, 1H, H-4′); ¹³C-NMR(CDCl₃): δ (ppm); 178.50, 177.90 (2C, C-4, C-9); 148.5 (C-2′); 146.8(C-5′); 141.8 (C-6 or C-7); 134.9 (C-6 or C-7); 131.8 (2C, C-4a, C-8a);130.09, 127.64 (2C, C-5, C-8); 114.80 (C-3′); 114.11 (C-4′); IR (KBr): ν(cm⁻¹); 1675, 1650 (C═O).

EXAMPLE 564,9-Dihydro-4,9-dioxo-2-(2-furyl)-5-methoxynaphtho-[2,3-d]thiazole or4,9-Dihydro-4,9-dioxo-2-(2-furyl)-8-methoxynaphtho-[2,3-d]thiazole

Under an inert atmosphere, to 3.64 g (12.9 mmol) of a mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methoxynaphthalene and2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methoxynaphthalene, 140 mL of anaqueous solution containing 7.74 g (32.2 mmol) of nonahydrated sodiumsulfate are added. The suspension so obtained is heated at 82° C. untilan “ink blue” solution is obtained; 2.1 mL (25.8 mmol) of 2-furaldehydeare then added to the reaction medium. The mixture gradually becomesbrick red. After 1.25 h, 6.73 g (38.7 mmol) of sodium hydrosulfite areadded to the reaction mixture, a chestnut brown precipitate graduallyappears. The precipitate is filtered at high temperature through frittedglass and washed with water. The crude product is recrystallized in DMF.A second recrystallization is carried out in dichloromethane. Thefiltrate, after evaporation at a reduced pressure, is purified over acake (support: silica 6-35 μm; conditioning: CH₂Cl₂/heptane, 80/20;eluant: CH₂Cl₂/MeOH, 100/0 to 90/10). The solid obtained is washed withheptane, uncolored over animal charcoal in dichloromethane, and filteredthrough micropores to produce, after evaporation at a reduced pressure,0.32 g of4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-methoxynaphtho[2,3-d]thiazole or4,9-dihydro-4,9-dioxo-2-(2-furyl)-8-methoxynaphtho[2,3-d]thiazole in theform of orange crystals.

Yield: 8%; Melting point: >260° C.; Rf: 0.60 (CH₂Cl₂/MeOH, 98/2); MS(APcI+): m/z 312 (M⁺H⁺); ¹H-NMR (CD₂Cl₂): (ppm); 7.78 (dd, 1H, H-8 orH-5, J_(H7-H8)=7.63 Hz, J_(H6-H8)=1.22 Hz); 7.65 (t, 1H, H-7 or H-6,J_(H7-H8) # J_(H6-H7)=7.62 Hz); 7.60 (dd, 1H, H-5′, J_(H4′-H5′)=1.53 Hz,J_(H3′-H5′)=0.92 Hz); 7.33 (dd, 1H, H-6 or H-7 in [sic; at] a of themethoxy group, J_(H6-H7)=8.24 Hz, J_(H6-H8) or J_(H5-H7)=0.92 Hz); 7.31(s, 1H, H-3′); 6.59 (dd, 1H, H-4′, J_(H3′-H4′)=3.67 Hz, J_(H4′-H5′)=1.83Hz); 3.96 (s, 3H, OCH ₃); IR (KBr) ν (cm⁻¹); 3112 (C—H); 1674 (C═O);1655 (C═N).

EXAMPLE 574,9-Dihydro-4,9-dioxo-2-(2-furyl)-5-hydroxynaphtho-[2,3-d]thiazole or4,9-Dihydro-4,9-dioxo-2-(2-furyl)-8-hydroxynaphtho-[2,3-d]thiazole

To a solution of4,9-dihydro-4,9-dioxo-2-(2-furyl)-5-methoxynaphtho[2,3-d]thiazole or4,9-dihydro-4,9-di-oxo-2-(2-furyl)-8-methoxynaphtho[2,3-d]thiazole (230mg, 0.73 mmol) in 20 mL of acetic acid, 0.90 mL of 47% hydrobromic acid(7.69 mmol) is added. The reaction mixture under stirring is heated toreflux for 5 h. After return to ambient temperature, water (30 mL) isadded to the reaction medium. This solution is then extracted withdichloromethane. The organic phase is washed with water until the pH isneutral. After drying on calcium chloride, the organic phase isevaporated at a reduced pressure. The raw reaction product is purifiedover a cake (support: silica 6-35 μm; eluant CH₂Cl₂). The product,dissolved in dichloromethane, is uncolored over animal charcoal. Afterwashing with heptane, 110 mg of 4,9-dihydro-4,9-dioxo-2-(2-furyl)-5(or8)hydroxynaphtho[2,3-d]thiazole in the form of an orange powder areobtained.

Yield: 50%; Melting point: 257° C.; Rf: 0.50 (CH₂Cl₂); MS (APcI+): m/z298 (M⁺H⁺); ¹H-NMR (CD₂Cl₂): δ (ppm); 12.25 (s, 1H, OH); 7.77 (dd, 1H,H-8 or H-5, J_(H7-H8) or J_(H5-H6)=7.63 Hz, J_(H5-H7)=1.22 Hz); 7.70(dd, 1H, H-5′, J_(H4′-H5′)=1.84 Hz, J_(H3′-H5′)=0.92 Hz); 7.68 (t, 1H,H-7 or H-6 at b of the hydroxy group, J_(H7-H8) or J_(H5-H6)=7.63 Hz,J_(H6-H7)=8.23 Hz); 7.41 (d, 1H, H-3′, J_(H3′-H4′)=3.67 Hz); 7.34 (dd,1H, H-6 or H-7 at a of the hydroxy group, J_(H6-H7)=8.23 Hz, J_(H6-H8)or J_(H5-H7)=1.22 Hz); 6.69 (dd, 1H, H-4′, J_(H3′-H4′)=3.66 Hz,J_(H4′-H5′)=1.83 Hz); ¹³C-NMR (CD₂Cl₂): δ (ppm); 183.72 (1C, C-4 orC-9); 177.73 (1C, C-9 or C-4); 164.31 (1C, C-5 or C-8); 163.45 (1C,C-2); 155.15 (1C, C-2′); 148.41 (1C, C-3a); 146.68 (1C, C-5′); 142.00(1C, C-9a); 137.07 (1C, C-7 or C-6 at β of the hydroxy group); 133.76(1C, C-8a or C-4a); 125.74 (1C, C-8 or C-5); 120.32 (1C, C-6 or C-7 at αof the hydroxy group); 115.69 (1C, C-4a or C-8a); 113.75 and 114.07 (2C,C-3′ and C-4′); IR (KBr): ν (cm⁻¹); 3400 (OH); 3124 (C—H); 1644 (C═O);1584 (C—C).

EXAMPLES 58 AND 594,9-Dihydro-4,9-dioxo-2-(2-furyl)-6-methoxynaphtho-[2,3-d]thiazole and4,9-Dihydro-4,9-dioxo-2-(2-furyl)-7-methoxynaphtho-[2,3-d]thiazole

Under an inert atmosphere, to 2.00 g (7.1 mmol) of a mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-methoxynaphthalene and3-amino-2-bromo-1,4-dihydro-1,4-dioxo-6-methoxynaphthalene, 75 mL of anaqueous solution containing 4.25 g (17.7 mmol) of nonahydrated sodiumsulfide are added. The suspension so obtained is heated at 80° C.; thenaphthoquinone dissolves gradually to produce a “ink blue” solution; 1.2mL (14.2 mmol) of 2-furaldehyde are then added to the reaction medium.The mixture gradually becomes brick red. After 1½ h and cooling to 50°C., 2.45 g (14.2 mmol) of sodium hydrosulfite are added to the reactionmixture, and a chestnut brown precipitate appears. The precipitate ishot filtered through fritted glass and washed with water until thewashing waters are colorless. After drying in the oven under vacuum, thecrude product is purified over a silica gel cake (silica 6-35 mm, eluantCH₂Cl₂/MeOH, 98/2); 1.15 g (3.7 mmol) of the mixture of4,9-dihydro-4,9-dioxo-2-(2-furyl)-6-methoxynaphtho-[2,3-d]thiazole and4,9-dihydro-4,9-dioxo-2-(2-furyl)-7-methoxynaphtho[2,3-d]thiazole [areobtained].

The separation of the two isomers is performed by three successivelow-pressure chromatographies of the mixture (silica 6-35 μm, eluantCH₂Cl₂/AcOEt, 99/1). After color removal and recrystallization of eachisomer in dichloromethane, 0.210 g of orange crystals of the more polarproduct and 0.300 g of orange crystals of the less polar product areobtained.

The More Polar Product

Yield: 9.5%; Melting point: >260° C.; Rt: 0.58 (CH₂Cl₂/AcOEt, 90/10); MS(I.E.): m/z 311 (M⁺)^(·); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.22 (d, 1H, H-8 orH-5, J_(H5-H6) or J_(H7-H8)=8.85 Hz); 7.69 (sl, 1H, H-5′); 7.66 (d, 1H,H-5 or H-8 at a of the methoxy group, J_(H5-H7) or J_(H6-H8)=2.74 Hz);7.40 (d, 1H, H-3′, J_(H3′-H4′)=3.66 Hz); 7.27 (dd, 1H, H-7 or H-6,J_(H5-H6) or J_(H7-H8)=8.55 Hz, J_(H6-H8) or J_(H5-H7)=2.45 Hz); 6.68(dd, 1H, H-4′, J_(H3′-H4′)=3.66 Hz, J_(H4′-H5′)=1.83 Hz); 3.98 (s, 3H,CH₃O at 6 or 7); I.R. (KBr): ν (cm¹); 1675 (C═O), 1650 (C═N), 1589.

The Less Polar Product

Yield: 13.5%; Melting point: >260° C.; Rf: 0.68 (CH₂Cl₂/AcOEt, 90/10);MS (I.E.): m/z 311 (M⁺)^(·); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.15 (d, 1H, H-8or H-5, J_(H5-H6) or J_(H7-H8)=8.55 Hz); 7.73 (d, 1H, H-5 or H-8 at a ofthe methoxy group, J_(H5-H7) or J_(H6-H8)=2.75 Hz); 7.68 (d, 1H, H-5′,J_(H4′-H5′)=1.83 Hz); 7.38 (d, 1H, H-3′, J_(H3′-H4′)=3.67 Hz); 7.25 (dd,1H, H-7 or H-6, J_(H5-H6) or J_(H7-H8)=8.55 Hz, J_(H6-H8) orJ_(H5-H7)=2.75 Hz); 6.68 (dd, 1H, H-4′, J_(H3′-H4′)=3.66 Hz,J_(H4′-H5′)=1.83 Hz); 3.99 (s, 3H, CH₃O at 6 or 7); I.R. (KBr): ν(cm⁻¹); 1681 (C═O), 1645 (C═N), 1586.

EXAMPLES 60 AND 614,9-Dihydro-4,9-dioxo-2-furyl-6-methylnaphtho[2,3-d]-thiazole and4,9-Dihydro-4,9-dioxo-2-furyl-7-methylnaphtho[2,3-d]-thiazole

Synthesis Intermediates:

2-Amino-3-chloro-1,4-dihydro-1,4-dioxo-6-methylnaphthalene and

2-Amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene

To a solution consisting of 6.00 g (25 mmol, 1.0 eq) of a mixture of2-chloro-1,4-dihydro-1,4-dioxo-6-methylnaphthalene (CAS No. 87 170-60-3)and 2-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene (CAS No. 87170-61-4) along with 250 mL of glacial acetic acid, 2.60 g (40 mmol, 1.6eq) of sodium nitride dissolved in 16 mL of distilled water are added ina single aliquot. This mixture is heated at 80° C. for 5 h; its colorchanges from yellow to orange. After cooling, the reaction medium isevaporated to dryness, and the raw product obtained is purified on asilica bed (support: silica 6-35 μm, d 10 cm, h 5 cm, solid deposit,eluant: heptane/ethyl acetate, 92/8) to produce, after evaporation ofthe solvent, 0.44 g of a mixture of2-amino-3-chloro-1,4-dihydro-1,4-dioxo-6-methylnaphthalene and2-amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene in the formof red crystals.

Yield: 8%; Rf: 0.38 (heptane/diethyl acetate, 70/30); MS (APcI+): m/z222/226 (M⁺H⁺); ¹H-NMR (CDCl₃): δ (ppm); 7.99 and 7.95 (2d, 2H, protonsat b of CH₃, J=7.93 Hz); 7.87 (s, 2H, protons at a of CH₃); 7.56 and7.48 (2d, 2H, protons at a of CH₃); 2.49 and 2.47 (2s, 6H, 2×CH₃).

4,9-Dihydro-4,9-dioxo-2-furyl-6-methylnaphtho[2,3-d]-thiazole and

4,9-Dihydro-4,9-dioxo-2-furyl-7-methylnaphtho[2,3-d]-thiazole

EXAMPLES 60 AND 61

To a solution consisting of 1.3 g (5.4 mmol, 6.0 eq) of nonahydratedsodium sulfide and 3.2 mL of a sodium hydroxide solution preparedearlier at pH 10.7, 0.2 g (0.9 mmol, 1.0 eq) of a mixture of2-amino-3-chloro-1,4-dihydro-1,4-dioxo-6-methylnaphthalene and2-amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene is added.This suspension, heated at 45° C., leads to a blue solution within 30min; 149 μL (1.8 mmol, 2.0 eq) of 2-furaldehyde are then added and,after 15 min, 97 μL (1.7 mmol, 1.9 eq) of glacial acetic acid are addedat 55° C. The reaction mixture, which has turned chestnut brown, isextracted with 6×100 mL of dichloromethane. The aqueous phases arecombined, dried over magnesium sulfate, filtered, and evaporated todryness. The product obtained is purified over a silica bed (support:silica 6-35 μm, 15 cm h, 5 cm φ, solid deposit, eluant: heptane/ethylacetate, 90/10) to produce, after evaporation of the solvent, 0.13 g ofthe mixture of4,9-dihydro-4,9-dioxo-2-furyl-6-methylnaphtho-[2,3-d]-thiazole and4,9-dihydro-4,9-dioxo-2-furyl-7-methylnaphtho-[2,3-d]thiazole, [of] thetwo isomers, in the form of orange crystals.

The isomers are then separated by preparative plates (support: alumina,eluant: dichloromethane/heptane, 70/30).

Yield: 48.8% (mixture of the two isomers).

The More Polar Product

Rf: 0.42 (dichloromethane/heptane, 70/30, alumina); MS (APcI+): m/z 296(M⁺H⁺); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.20 (d, 1H, H-5 or H-8 at b of CH₃,J_(H5-H6) or J_(H7-H8)=7.93 Hz); 8.05 (m, 1H, H-5 or H-8 at a of CH₃);7.73 (dd, 1H, H-5′, J_(H4′-H5′)=1.83 Hz, J_(H3′-H5′)=0.61 Hz); 7.67 (d,1H, H-6 or H-7, J_(H5-H6) or J_(H7-H8)=7.94 Hz, at a of CH₃); 7.44 (dd,1H, H-3′, J_(H3′-H4′)=3.67 Hz, J_(H3′-H5′)=0.61 Hz); 6.72 (dd, 1H, H-4′,J_(H3′-H4′)=3.66 Hz, J_(H4′-H5′)=1.83 Hz); 2.57 (s, 3H, CH₃); ¹³C-NMR(CD₂Cl₂): δ (ppm); 146.41 (1C, C-5′); 135.31 (1C, C-6 or C-7, at a ofCH₃); 127.99 (1C, C-5 or C-8); 127.55 (1C, C-5 or C-8); 113.70 (1C,C-3′); 113.59 (1C, C-4′); 21.94 (1C, CH₃);

The Less Polar Product

Rf: 0.50 (dichloromethane/heptane, 70/30, alumina); MS (APcI+): m/z 296(M⁺H⁺); ¹H-NMR (CD₂Cl₂): δ (ππμ); 8.01 (m, 2H, H-5, H-8); 7.60 (dd, 1H,H-5′, J_(H4′-H5′)=1.83 Hz, J_(H3′-H5′)=0.61 Hz); 7.53 (d, 1H, H-6 orH-7, J_(H5-H6) or J_(H7-H8)=7.33 Hz, at a of CH₃); 7.31 (dd, 1H, H-3′,J_(H3′-H4′)=3.66 Hz, J_(H3′-H5′)=0.61 Hz); 6.60 (dd, 1H, H-4′,J_(H3′-H4′)=3.66 Hz, J_(H4′-H5′)=1.83 Hz); 2.46 (s, 3H, CH₃); ¹³C-NMR(CD₂Cl₂): δ (ppm); 176.28 (2C, C═O); 145.99 (1C, C-5); 134.64 (1C, C-6or C-7, at a of CH₃); 127.94 (1C, C-5 or C-8); 126.83 (1C, C-5 or C-8);113.24 (1C, C-3′); 113.18 (1C, C-4′); 21.74 (1C, CH₃).

EXAMPLES 62 AND 634,9-Dihydro-4,9-dioxo-6-methyl-2-phenylnaphtho[2,3-d]thiazole and4,9-Dihydro-4,9-dioxo-7-methyl-2-phenylnaphtho[2,3-d]thiazole

To a solution consisting of 1.3 g (5.4 mmol, 6.0 eq) of nonahydratedsodium sulfide and 3.2 mL of a sodium hydroxide solution, which wasfirst prepared at a pH of 10.7, 0.5 g (0.9 mmol, 1.0 eq) of a mixture of2-amino-3-chloro-1,4-dihydro-1,4-dioxo 6-methylnaphthalene and2-amino-3-chloro-1,4-dihydro-1,4-dioxo-7-methylnaphthalene is added.This solution, when heated at 45° C., turns blue within 30 min; 184 μL(1.8 mmol, 2.0 eq) of benzaldehyde are then added to the reactionmedium. The mixture, when heated at 55° C., turns green within 30 min.After the addition of 291 μL (5.0 mmol, 5.5 eq) of glacial acetic acid,a chestnut brown precipitate forms, which is filtered through frittedglass, then washed with dichloromethane. The raw product obtained ispurified on a silica bed (support: silica 6-35 μm, d=5 cm, h=5 cm, soliddeposit, eluant: heptane/ethyl acetate, 90/10) to produce, afterevaporation of the solvents, 90 mg of the mixture of4,9-dihydro-4,9-dioxo-6-methyl-2-phenylnaphtho[2,3-d]-thiazole and4,9-dihydro-4,9-dioxo-7-methyl-2-phenylnaphtho[2,3-d]thiazole in theform of yellow crystals. These isomers are separated on preparativeplates (support: alumina, eluant: dichloromethane/heptane, 70/30).

Yield: 33% (mixture of the two isomers).

The More Polar Product Rf: 0.50 (dichloromethane/heptane, 70/30,alumina); MS (APcI+): m/z 306 (M⁺H⁺); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.10 (d,1H, H-5 or H-8, J_(H5-H6) or J_(H7-H8)=7.63 Hz); 8.03 (m, 2H, H-2′ andH-6′); 7.93 (bs, 1H, H-5 or H-8, at a of CH₃); 7.55 (d, 1H, H-6 or H-7,J_(H5-H6) or J_(H7-H8)=7.93 Hz); 7.46 (m, 3H, H-3′, H-4′, H-5′); 2.45(s, 3H, CH₃); ¹³C-NMR (CD₂Cl₂): δ (ppm); 135.36 (1C, C-6 or C-7); 132.60(1C, C-4′); 129.65 (2C, C-2′, C-6′); 128.01 (1C, C-5 or C-8); 127.90(2C, C-3′, C-5′); 127.55 (1C, C-5 or C-8); 21.93 (1C, CH₃);

The Less Polar Product

Rf: 0.62 (dichloromethane/heptane, 70/30, alumina); MS (APcI+): m/z 306(M⁺H⁺); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.09-8.00 (m, 4H, H-5, H-8, H-2′,H-6′). 7.53 (d, 1H, H-6 or H-7, J_(H5-H6) or J_(H7-H8)=7.93 Hz); 7.46(m, 3H, H-3′, H-4′, H-5′); 2.46 (s, 3H, CH₃); ¹³C-NMR (CD₂Cl₂): δ (ppm);134.98 (1C, C-6 or C-7); 132.59 (1C, C-4′); 129.66 (2C, C-2′, C-6′);128.36 (1C, C-5 or C-8); 127.90 (2C, C-3′, C-5′); 127.25 (1C, C-5 orC-8); 22.0 (1C, CH₃);

EXAMPLES 64 AND 654,9-Dihydro-4,9-dioxo-2-furyl-5-methylnaphtho[2,3-d]-thiazole and4,9-Dihydro-4,9-dioxo-2-furyl-8-methylnaphtho[2,3-d]-thiazole

Synthesis Intermediates:

2,3-Dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene

To 14.5 g (84 mmol, 1 eq) of 1,4-dihydro-1,4-dioxo-5-methylnaphthalene,200 mL of carbon tetrachloride, then 17.2 mL (337 mmol, 4 eq) ofbromine, are added. The solution turns red, then 22.94 g (168 mmol, 2eq) of sodium acetate are added. After 96 h of reflux, the reactionmedium is filtered, washed with carbon tetrachloride, and evaporated todryness; the product is purified on a cake (Φ=6.5 cm, height=5 cm,deposit=solid, support=silica, eluant CH₂Cl₂); after evaporation todryness, an orangish chestnut-brown paste is obtained. A firstcrystallization with dichloromethane yields 8.25 g of2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene in the form ofyellow crystals; a second recrystallization with acetonitrile produces11.90 g of 2,3-dibromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene in theform of yellow crystals.

Yield: 72%; Rf: 0.70 (ethyl acetate/heptane, 50/50); MS (APcI−): m/z328, 330, 332 (M⁻); ¹H-NMR (CDCl₃): δ (ppm); 8.11 (dd, 1H, H-8,J_(H7-H8)=7.02 Hz, J_(H6-H6)=1.53 Hz); 7.63 (m, 2H, H-6, H-7); 2.76 (s,3H, CH₃); IR (KBr): ν (cm⁻¹); 1670 (C═O); 1570 (C═C);

2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene

2-Amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methylnaphthalene

To 8 g (24 mmol, 1 eq) of 2,3-dibromo-1,4-dihydro-1,4-dioxonaphthalene,200 mL of glacial acetic acid (3.5 mmol, 6.85 eq), then 2.52 g (38 mmol)of sodium nitride dissolved in 17.5 mL of water are added. After 12 h at70° C., the solution turns red. The reaction mixture is cooled andevaporated to dryness, the product is purified on a cake (Φ=5 cm, h=5cm, deposit=solid, support=silica, eluant=concentration gradient ofethyl acetate/heptane 10/90 then 20/80). 525 mg of the mixture2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene and of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methylnaphthalene in the form ofred-orangish crystals are obtained.

Yield: 8%; Rf: 0.58 (ethyl acetate/heptane, 50/50); MS (APcI−): m/z 264266(M⁻); ¹H-NMR (CDCl₃): δ (ppm); 8.12 (d, 1H, H-5 or H-8, J_(H7-H8) orJ_(H5-H6)=7.32 Hz); 7.58 (t, 1H, H-6 or H-7, J_(H5-H6) or J_(H7-H8)=7.63Hz); 7.44 (d, 1H, H-6 or H-7, J_(H5-H6) or J_(H7-H8)=7.63 Hz); 2.74 (s,3H, CH₃).

4,9-Dihydro-4,9-dioxo-2-furyl-5-methylnaphtho[2,3-d]-thiazole and

4,9-Dihydro-4,9-dioxo-2-furyl-8-methylnaphtho[2,3-d]-thiazole

To a solution consisting of 1.35 g (5.63 mmol) of nonahydrated sodiumsulfide and 3.38 mL (1.8×10⁻¹ mol) of a sodium hydroxide solution, whichwas first prepared with pH=9, 0.25 g (0.93 mmol) of a mixture of2-amino-3-bromo-1,4-dihydro-1,4-dioxo-5-methylnaphthalene and2-amino-3-bromo-1,4-dihydro-1,4-dioxo-8-methylnaphthalene is added. Thissuspension is heated at 45° C. and it turns blue after 40 min; 156 mL(1.87 mmol) of 2-furaldehyde are added; after 15 min, 102 μL (1.178mmol) of glacial acetic acid are added at 55° C. The reaction mixture,which has turned chestnut brown, is then extracted with 2×100 mL ofdichloromethane, dried over magnesium sulfate, filtered, and evaporatedto dryness. An alumina cake is then prepared (eluant: concentrationgradient: 50/50 to 70/30 in dichloromethane/heptane.

The yield then consists of 51 mg (18%) of a mixture of4,9-dihydro-4,9-dioxo-2-furyl-5-methylnaphtho[2,3-d]thiazole and4,9-dihydro-4,9-dioxo-2-furyl-8-methylnaphtho[2,3-d]-thiazole. Theseparation of the isomers on a preparative plate (support: alumina,eluant: dichloromethane/heptane) produces a more polar product and aless polar product.

The Less Polar Product

Rf: 0.61 (dichloromethane/heptane, 70/30, alumina); MS (APcI+): m/z 296(M⁺H⁺); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.07 (d, 1H, H-5 or H-8 at g of CH₃,J_(H5-H6) or J_(H7-H8)=9.55 Hz); 7.58 (m, 3H, H-6 and H-7 at α and β ofCH₃ and H-5′); 7.32 (d, 1H, H-3′, J_(H3′-H4′)=3.32 Hz); 6.60 (dd, 1H,H-4′, J_(H3′-H4′)=3.1 Hz, J_(H4′-H5′)=1.2 Hz); 2.77 (s, 3H, CH₃);¹³C-NMR (CD₂Cl₂): δ (ppm); 145.24 (1C, C-5′); 137.82-132.24 (2C, C-6 andC-7); 124.90 (1C, C-5 or C-8); 112.54 and 112.44 (2C, C-3′ and C-4′).

The More Polar Product

Rf: 0.53 (dichloromethane/heptane, 70/30, alumina); MS (APcI+): m/z 296(M⁺H⁺); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.07 (d, 1H, H-5 or H-8, J_(H5-H6) orJ_(H7-H8)=4.98 Hz, J_(H5-H7) or J_(H6-H8)=1.5 Hz); 7.60 (m, 3H, H-6 andH-7 at α and β of CH₃ and H-5′); 7.32 (d, 1H, H-3′, J_(H3′-H4′)=3.73Hz); 6.45 (dd, 1H, H-4′, J_(H3′-H4′)=3.32 Hz, J_(H4′-H5′)=1.66 Hz); 2.77(s, 3H, CH₃); ¹³C-NMR (CD₂Cl₂): δ (ppm); 189.69 and 184.57 (2C, C-4 andC-9); 145.38 (1C, C-5′); 129.29 (1C, C-6 or C-7 at β of CH₃);126.04-132.24 (1C, C-6 or C-7 at a of CH₃); 123.45 (1C, C-5 or C-8 at δof CH₃); 113.67 and 113.57 (2C, C-3′ and C-4′); 23.39 (1C, CH₃).

EXAMPLES 66 AND 674,9-Dihydro-4,9-dioxo-5-methyl-2-phenylnaphtho[2,3-d]thiazole and4,9-Dihydro-4,9-dioxo-8-methyl-2-phenylnaphtho[2,3-d]thiazole

To a solution consisting of 1.35 g (5.63 mmol, 6 eq) of nonahydratedsodium sulfide and 3.38 mL (890 mmol, 193 eq) of a sodium hydroxidesolution which had first been prepared at pH=9, 0.25 g (0.93 mmol) ofthe mixture of 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-6-methylnaphthaleneand 2-amino-3-bromo-1,4-dihydro-1,4-dioxo-7-methylnaphthalene isobtained. This suspension, when heated at 45° C., turns blue after 30min; 191 mL (1.87 mmol, 2 eq) of benzaldehyde are added; after 15 min,102 mL (1.78 mmol) of glacial acetic acid are then added at 55° C. Thereaction mixture, which has turned chestnut brown, is extracted with3×100 mL of dichloromethane, washed until neutral, and dried overmagnesium sulfate to produce 38 mg (13%) of raw product. Afterseparation of the two isomers on a preparative plate (support alumina,eluant dichloromethane/heptane 70/30), two products are obtained:4,9-dihydro-4,9-dioxo-5-methyl-2-phenylnaphtho[2,3-d]-thiazole and4,9-dihydro-4,9-dioxo-8-methyl-2-phenylnaphtho[2,3-d]thiazole.

The Less Polar Product

Rf: 0.58 (dichloromethane/heptane, 70/30, alumina); MS (IE): m/z 305(M⁺)^(·); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.07 (m, 3H, H-2′, H-6′, H-5 orH-8); 7.61 (m, 2H, H-6, H-7); 7.49 (m, 2H, H-3′, H-5′); 7.30 (m, 1H,H-4′); 2.76 (s, 3H, CH₃).

The More Polar Product

Rf: 0.51 (dichloromethane/heptane, 70/30, alumina); MS (IE): m/z 305(M⁺)^(·); ¹H-NMR (CD₂Cl₂): δ (ppm); 8.07 (m, 3H, H-2′, H-6′, H-5 or H-8at g of CH₃); 7.60 (m, 2H, H-6, H-7); 7.49 (m, 2H, H-3′, H-5′); 7.30 (m,1H, H-4′); 2.77 (s, 3H, CH₃).

Example a 4,9-Dihydro-4,9-dioxo-2-methyl-1H-naphtho[2,3-d]imidazole

Reference: C.A. 67 97905t; Yield: 76%; Melting point: >260° C.; Rf: 0.44(CH₂Cl₂/methanol, 97/3); MS (I.E.): m/z 212 (M⁺.); ¹H-NMR (DMSO d₆): δ(ppm); 13.74 (s, 1H, NH); 8.05 (dd, 2H, H-5, H-8,J_(H5-H6)=J_(H7-H8)=8.85 Hz; J_(H5-H7) =J _(H6-H8)=1.73 Hz); 7.82 (m,2H, H-6, H-7); 2.45 (s, 3H, CH₃); ¹³C-NMR (DMSO d₆): δ (ppm); 178.15;176.53 (2C, C-4, C-9); 153.80 (1C, C-2); 137.14 (1C, C-3a); 133.98,133.99 (2C, C-6, C-7); 133.27, 133.10, 132.84 (3C, C-8a, C-9a, C-4a);126.82 (2C, C-5, C-8); 14.01 (1C, CH₃); IR (KBr): ν (cm⁻¹); 3134 to 2897(NH); 1678, 1672 (C═O).

Example b4,9-Dihydro-4,9-dioxo-2-methyl-1-phenyl-1H-naphtho-[2,3-d]imidazole

Reference: C.A. 67 97905t; Yield: 72%; Melting point: 242° C.; Rf: 0.43(CH₂Cl₂/methanol, 99/1); MS (I.E.): m/z 288 (M⁺.); ¹H-NMR (DMSO, d₆): δ(ppm); 8.23 (d, 1H, H-5 or H-8, J_(H5-H6) or J_(H7-H8)=6.71 Hz); 7.90(d, 1H, H-5 or H-8, J_(H-5-H6) or J_(H7-H8)=6.71 Hz); 7.68 (m, 3H, H-3′,H-4′, H-5′); 7.60 (m, 2H, H-6, H-7); 7.37 (m, 2H, H-2′, H-6′); 2.40 (s,3H, CH₃); ¹³C-NMR (CDCl₃: δ (ppm); 179.13, 175.03 (2C, C-4, C-9); 153.66(1C, C-2); 143.14 (1C, C-1′); 135.11 (1C, C-3a); 133.68, 133.51 (2C,C-6, C-7); 133.15, 133.01, 132.63 (3C, C-8a, C-9a, C-4a); 129.95, 129.69(3C, C-3′, C-4′, C-5′); 126.93, 126.76, 126.43 (4C, C-2′, C-6′, C-5,C-8); 13.77 (1C, CH₃); IR (KBr): ν (cm⁻¹); 1674, 1663 (C═O).

Examiple c4,9-Dihydro-4,9-dioxo-2-methyl-1-phenyl-1H-naphtho[2,3-d]imidazolesulfate

Reference: C.A. 68 8764b; Yield: 47%; Melting point: >260° C.; Rf: 0.53(CH₂Cl₂/methanol, 97.5/2.5); ¹H-NMR (DMSO, d₆): δ (ppm); 8.11 (dd, 1H,H-5 or H-8, J_(H5-H6) or J_(H7-H8)=8.85 Hz; J_(H5-H7) or J_(H6-H8)=1.73Hz); 8.00 (dd, 1H, H-5 or H-8, J_(H5-H6) or J_(H7-H8)=8.85 Hz; J_(H5-H7)or J_(H6-H8)=1.73 Hz); 7.94 (m, 2H, H-6, H-7); 7.82 (m, 2H, H-2′, H-6′);7.51 (m, 3H, H-3′, H-4′, H-5′); 5.54 (s, 1H, NH+); 2.30 (s, 3H, CH₃); IR(KBr): ν (cm⁻¹); 3414-2400 (broad NH⁺ band); 1736, 1681 (C═O).

Example d 4,9-Dihydro-4,9-dioxo-1,2-dimethyl-1H-naphtho[2,3-d]imidazole

Reference: C.A. 66 104957w; Yield: 70%; Melting point: >253° C.; Rf:0.49 (CH₂Cl₂/methanol, 98/2); MS (I.E.): m/z 226 (M⁺.); ¹H-NMR (CDCl₃):δ (ppm); 8.21, 8.09 (2m, 2H, H-5, H-8); 7.70 (m, 2H, H-6, H-7); 4.01 (s,3H, CH₃); 2.56 (s, 3H, CH₃); ¹³C-NMR (CDCl₃: δ (ppm); 179.22, 178.44(2C, C-4, C-9); 154.46 (1C, C-2); 134.18, 134.11 (2C, C-6, C-7); 133.37,133.17 (2C, C-4a, C-8a); 127.37, 126.75 (2C, C-5, C-8); 32.74 (1C, CH₃);13.64 (1C, CH₃); IR (KBr): ν (cm⁻¹); 1674 (C═O).

Example e 4,9-Dihydro-4,9-dioxo-2-phenyl-1H-naphtho[2,3-d]imidazole

Reference: C.A. 68 8764b; Yield: 34%; Melting point: >260° C.; Rf: 0.51(CH₂Cl₂/diethyl acetate, 90/10); MS (I.E.): m/z 274 (M⁺); ¹H-NMR (DMSOd₆): δ (ppm); 14.40 (s, 1H, NH); 8.26 (m, 2H, H-5, H-8); 8.12 (m, 2H,H-2′, H-6′); 7.87 (m, 2H, H-6, H-7); 7.54 (m, 3H, H-3′, H-4′, H-5′);¹³C-NMR (DMSO d₆): δ (ppm); 179.13, 175.03 (2C, C-4, C-9); 152.60 (1C,C-2); 133.89 (2C, C-6, C-7); 132.60 (2C, C-9a, C-3a); 130.00 (2C, C-4a,C-8a); 129.03 (3C, C-3′, C-4′, C-5′); 126.82, 126.32 (4C, C-5, C-8,C-2′, C-6′); IR (KBr): ν (cm⁻¹); 3232 (NH); 1681, 1664 (C═O).

Example f 4,9-Dihydro-4,9-dioxo-2-phenylnaphtho[2,3-d]oxazole

Reference: C.A. 87 53134z; Yield: 75%; Melting point: >260° C.; Rf: 0.60(CH₂Cl₂/Heptane, 80/20); MS (I.E.): m/z 275 (M⁺.); ¹H-NMR (CDCl₃): δ(ppm); 8.33 (d, 2H, H-2′, H-6′, J_(H2′-H3′)=J_(H5′-H6′)=6.71 Hz); 8.27(m, 2H, H-5, H-8); 7.82 (m, 2H, H-6, H-7); 7.58 (m, 3H, H-3′, H-4′,H-5′); ¹³C-NMR (CDCl₃: δ (ppm); 178.50, 173.05 (2C, C-4, C-9); 167.76(1C, C-2); 134.52, 132.99 (2C, C-6, C-7); 129.21 (3C, C-3′, C-4′, C-5′);128.33 (2C, C-2′, C-6′); 127.50, 127.04 (2C, C-5, C-8); IR (KBr): ν(cm⁻¹); 1693, 1678 (C═O).

Example g 4,9-Dihydro-4,9-dioxo-2-(4-methylphenyl)-naphtho[2,3-d]oxazole

Reference: C.A. 87 53134z; Yield: 44%; Melting point: >260° C.; Rf: 0.50(CH₂Cl₂); MS (I.E.): m/z 289 (M⁺); ¹H-NMR (CDCl₃): δ (ppm); 8.27 (m, 2H,H-5, H-8); 8.23 (d, 2H, H-2′, H-6′, J_(H2′-H3′)=J_(H5′-H6′)=8.24 Hz);7.81 (m, 2H, H-6, H-7); 7.38 (m, 2H, H-3′, H-5′); 2.46 (s, 3H, CH₃);¹³C-NMR (CDCl₃: δ (ppm); 178.77, 173.80 (2C, C-4, C-9); 165.51 (1C,C-2); 143.95 (1C, C-3a); 135.80 (1C, C-4′); 134.29, 132.12 (3C, C-1′,C-6, C-7); 131.70, 131.38 (2C, C-4a, C-8a); 129.93, 128.28 (4C, C-2′,C-3′, C-5′, C-6′); 127.44, 126.99 (2C, C-5, C-8); 122.41 (1C, C-1′);21.81 (1C, CH₃); IR (KBr): ν (cm⁻¹); 1668, 1678 (C═O).

Example h 4,9-Dihydro-4,9-dioxo-2-methylnaphtho[2,3-d]thiazole

Reference: C.A. 120 270267z; Yield: 11%; Melting point: >260° C.; Rf:0.41 (CH₂Cl₂/methanol, 99/1); MS (I.E.): m/z 229 (M⁺); ¹H-NMR (CDCl₃): δ(ppm); 8.33, 8.21 (2dd, 2H, H-5, H-8, J_(H5-H6)=J_(H7-H8)=8.85 Hz); 7.80(m, 2H, H-6, H-7); 2.91 (s, 3H, CH₃); ¹³C-NMR (CDCl₃): δ (ppm); 177.95,176.95 (2C, C-4, C-9); 173.86 (1C, C-2); 153.10 (1C, C-3a); 142.14 (1C,C-9a); 133.90, 133.51 (2C, C-6, C-7); 132.06, 131.72 (2C, C-4a, C-8a);127.29, 126.47 (2C, C-5, C-8); 19.83 (1C, CH₃); IR (KBr): ν (cm⁻¹);1677, 1655 (C═O).

Example i 2-Amino-4,9-dihydro-4,9-dioxonaphtho[2,3-d]thiazole

Reference: C.A. 120 270267z; Yield: 96%; Melting point: >260° C.; Rf:0.24 (CH₂Cl₂/methanol, 96/4); MS (I.E.): m/z 230 (MH⁺); ¹H-NMR (DMSOd₆): δ (ppm); 8.56 (s, 2H, NH₂); 8.03 (m, 2H, H-5, H-8); 7.83 (m, 2H,H-6, H-7); ¹³C-NMR (DMSO d₆): δ (ppm); 178.04, 177.31 (2C, C-4, C-9);173.45 (1C, C-2); 154.61 (1C, C-3a); 145.95 (1C, C-9a); 134.34, 134.03(2C, C-6, C-7); 133.18, 132.24 (2C, C-4a, C-8a); 126.99, 125.97 (2C,C-5, C-8); IR (KBr): ν (cm⁻¹); 3460, 3420 (NH₂), 1690, 1660 (C═O).

Example j 4,9-Dihydro-4,9-dioxo-2-phenylnaphtho[2,3-d]thiazole

Reference: C.A. 67 11450f; Yield: 68%; Melting point: 249° C.; Rf: 0.45(CH₂Cl₂); MS (I.E.): m/z 291 (M⁺); ¹H-NMR (CDCl₃): δ (ppm); 8.30, 8.21(2dd, 2H, H-5, H-8, J_(H5-H6)=J_(H7-H8)=8.85 Hz,J_(H6-H8)=J_(H5-H7)=1.73 Hz); 8.14 (m, 2H, H-2′, H-6′); 7.83 (m, 2H,H-6, H-7); 7.56 (m, 3H, H-3′, H-4′, H-5′); ¹³C-NMR (CDCl₃): δ (ppm);178.45, 172.67 (2C, C-4, C-9); 134.82, 134.44 (2C, C-6, C-7); 133.50,133.24, 132.74, 132.01 (4C, C-9a, C-1′, C-4a, C-8a); 129.75, 128.01 (5C,C-2′, C-3′, C-4′, C-5′, C-6′); 127.94, 127.18 (2C, C-5, C-8); IR (KBr):ν (cm⁻¹); 1675, 1660 (C═O).

Example k 4,9-Dihydro-4,9-dioxo-2-(2-pyridyl)-naphtho[2,3-d]thiazole

Reference: C.A. 109 130788t; Yield: 75%; Melting point: >260° C.; Rf:0.60 (CH₂Cl₂/methanol, 97/3); MS (I.E.): m/z 292 (M⁺); ¹H-NMR (CDCl₃): δ(ppm); 8.69 (d, 1H, H-6′, J_(H5′-H6′)=5.50 Hz); 8.47 (d, 1H, H-3′,J_(H3′-H4′)=5.50 Hz); 8.36, 8.26 (2dd, 2H, H-5, H-8,J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H5-H7)=J_(H6-H8)=1.73 Hz); 7.82 (m, 3H,H-4′, H-6, H-7); 7.46 (m, 1H, H-5′); ¹³C-NMR (CDCl₃): δ (ppm); 178.17,177.43 (2C, C-4, C-9); 158.76 (1C, Cquat); 151.11 (1C, C-6′); 147.86(1C, C-4′); 134.77, 134.31 (2C, C-6, C-7); 133.50, 132.74 (2C, C-4a,C-8a); 128.04, 127.16 (2C, C-5, C-8); 121.15 (1C, C-3′); 118.45 (1C,C-5′); IR (KBr): ν (cm⁻¹); 1688, 1667 (C═O).

Example l 4,9-Dihydro-4,9-dioxo-2-(4-pyridyl)-naphtho[2,3-d]thiazole

Reference: C.A. 109 130788t; Yield: 75%; Melting point: >260° C.; Rf:0.30 (CH₂Cl₂/methanol, 97/3); MS (I.E.): m/z 292 (M⁺.); ¹H-NMR (CDCl₃):δ (ppm); 8.84 (d, 2H, H-2′, H-6′, J_(H2′-H3′)=J_(H5′-H6′)=5.50 Hz);8.39, 8.26 (dd, 2H, H-5, H-8, J_(H5-H6)=J_(H7-H8)=8.85 Hz,J_(H6-H8)=J_(H5-H7)=1.73 Hz); 7.99 (d, 2H, H-3′, H-5′,J_(H2′-H3′)=J_(H5′-H6′)=5.50 Hz); 7.84 (m, 2H, H-6, H-7); ¹³C-NMR(CDCl₃): δ (ppm); 178.17, 172.50 (2C, C-4, C-9); 151.11 (2C, C-2′,C-6′); 134.77, 134.31 (2C, C-6, C-7); 133.50, 132.74, 132.01 (4C, C-9a,C-4′, C-4a, C-8a); 128.04, 127.16 (2C, C-5, C-8); 121.04 (2C, C-3′,C-5′); IR (KBr): ν (cm⁻¹); 1688, 1667 (C═O).

Example m 4,9-Dihydro-4,9-dioxo-2-pyrrolylnaphtho[2,3-d]thiazole

Reference: C.A. 109 130788t; Yield: 17%; Melting point: 208° C. (dec);Rf: 0.44 (CH₂Cl₂/ethanol, 99/1); MS (I.E.): m/z 280 (M⁺.); ¹H-NMR(CD₂Cl₂): δ (ppm); 9.85 (ls, 1H, NH); 8.21, 8.17 (2dd, 2H, H-5, H-8,J_(H5-H6)=J_(H7-H8)=8.85 Hz, J_(H5-H7)=J_(H6-H8)=1.73 Hz); 7.79 (m, 2H,H-6, H-7); 7.07 (m, 1H, H-5′); 6.96 (m, 1H, H-3′); 6.35 (m, 1H, H-4′);IR (KBr): ν (cm⁻¹); 3286 (NH); 1676, 1647 (C═O).

Example n 4,9-Dihydro-4,9-dioxo-2-(2-furyl)-naphtho[2,3-d]thiazole

Reference: C.A. 67 11450f; Yield: 48%; Melting point: >260° C.; Rf: 0.55(CH₂Cl₂/methanol, 99,5/0,5); MS (I.E.): m/z 281 (MH⁺); ¹H-NMR (CDC₃): δ(ppm); 8.37 (dd, 1H, H-5 or H-8, J_(H5-H6) or J_(H7-H8)=8.85 Hz,J_(H5-H7) or J_(H6-H8)=1.73 Hz); 8.23 (m, 1H, H-5 or H-8); 7.81 (m, 2H,H-6, H-7); 7.65 (d, 1H, H-5′, J_(H4′-H5′)=1.97 Hz); 7.46 (d, 1H, H-3′,J_(H3′-H4′)=3.94 Hz); 6.65 (dd, 1H, H-4′, J_(H3′-H4′)=3.94 Hz,J_(H4′-H5′)=1.97 Hz); ¹³C-NMR (CDCl₃): δ (ppm); 178.25, 177.90 (2C, C-4,C-9); 163.94 (1C, C-2); 155.25 (1C, C-2′); 148.00 (1C, C-3a); 145.93(1C, C-5′); 140.62 (1C, C-9a); 134.34, 134.09 (2C, C-6, C-7); 133.13,132.68 (2C, C-4a, C-8a); 127.83, 126.91 (2C, C-5, C-8); 113.80 (1C,C-3′); 113.34 (1C, C-4′); IR (KBr): ν (cm⁻¹); 1683, 1658 (C═O).

Pharmacological Properties:

The study of the compounds of the present invention and their possiblesalts has demonstrated that they possess different pharmacologicalproperties. Thus, most of the compounds have a selective tonic effect onveins, affecting the arterial system only at concentrations that aremuch greater than those producing activity on veins, except for somearteries, particularly cerebral arteries (carotid, basilar). Thecompounds reveal no affinity or very low affinity for a majority of theknown pharmacological membrane receptors. Moreover, they increase thecapillary resistance and decrease the vascular hyperpermeability inducedby certain inflammatory agents. These properties are demonstrated inmammals, such as hamsters, rats, guinea pigs, and rabbits, under invitro conditions (isolated vessels or vascular beds) and in vivo. Forthe in vitro studies, the compounds are dissolved in a pure aqueoussolution or an aqueous solution containing DMSO (dimethyl sulfoxide).For the in vivo studies, they are administered intravenously orintraperitoneally in the form of an aqueous solution that may or may notcontain DMSO, or by an oral route in suspension in 1%carboxymethylcellulose administered with a force-feeding probe at avolume of 10 mL/kg.

Pharmacological Study Models

Contractile Effects:

The contractile effects are measured in vitro under static conditions onvascular capacitance or resistance rings of saphenous, femoral, jugular,mesenteric, and caval veins . . . and on femoral, carotid, basilar, ormesenteric arteries, as well as the thoracic or abdominal aorta . . . inrats (Wistar, 200-250 g), rabbits (New Zealand, 2-2.5 kg), guinea pigs(Dunkin Hartley 250-300 g).

The rings are placed in a chamber for isolated organs (25 mL forcapacitance vessels and 2.5 mL for resistance vessels according toMulvany), and maintained under isometric conditions using two rigidthreads inserted inside the vessel, avoiding causing damage to theendothelium. The vessels are bathed in a modified Krebs solution (in mM:NaCl=118; KCl=4.6; CaCl₂=2.5; MgSO₄=1.2; KH₂PO₄=1.17; NaHCO₃=25;glucose=11), continuously aerated using a gaseous mixture of 95% O₂ and5% Co₂, at a pH=7.4, and regulated by thermostat at 37° C. The rings areadjusted to their optimal point as far as the tension-lengthrelationship is concerned. The tensions developed generate an electricalsignal through the intermediary of a force sensor (Wheatstone bridge).This signal is amplified before being either displayed on a Kipp & Zonenrecorder, or digitized to be processed by computer (IOS, EMKA). Thepharmacological studies are carried out after a few standardizedpreliminary contractile stimulations using a depolarizing solution(hyperpotassic type obtained by replacing NaCl with KCl in equimolarquantities), along with rinsings and periods of equilibration in a purephysiological solution. The presence of endothelium is verified by therelaxation induced by increasing the concentration of acetylcholineafter the stabilization of a vascular precontraction.

The forces of contraction developed by the vascular rings in response tothe different compounds are studied on quiescent or electricallystimulated vessels (5-8 Hz), by a “physiological” depolarizinghyperpotassic solution (KCl: 20, 40 mM), by noradrenaline (increasingconcentrations), [and by] serotonin (increasing concentrations).

The contractions are expressed in mg force or as a percentage of themaximum contraction at the time of the depolarization with a“physiological” hyperpotassic solution.

The contractile effects are also measured in vitro under dynamic flowconditions, by the pressure developed by the vascular beds that areperfused at a constant flow rate. At the mesenteric level, the selectiveeffect on veins is studied using the model of a double simultaneous andseparate infusion of the arterial and venous networks model developed byT. Warner (British J. Pharmacol., 1990, Vol. 99, pp. 427-433). Theseparation of the two networks is achieved by cutting the vessels andthe tissues along the intestinal border. The networks are perfused at 2mL.min⁻¹ with a Krebs solution (37.5° C.), which is aerated using 95% O₂and 5% CO₂. In vivo, the arterial and venous pressures are measured inthe anesthetized animal, under basal conditions and after circulatoryarrest caused by the swelling of a balloon catheter introduced at thelevel of the left atrium. During the cardiac arrest, the venous tone(average circulatory filling pressure at a constant blood volume) iscalculated from the venous and arterial pressures measured atequilibrium and corrected as a function of the relative differences incompliance between these two networks (Samar & Coleman, Am. J. Physiol.,1978, Vol. 234: pp. H94-100; Yamamoto et al., Am. J. Physiol., 1980,Vol. 238: pp. H823-828).

In the conscious animal, the arterial pressures are measured accordingto the classical method derived from Riva Rocci, by the analysis of theacoustical wave transmitted at the arterial level and transformed by aceramic piezo transducer placed on the tail of the rat, downstream froma sleeve that is automatically inflated by a pressure generator. At themicrocirculatory level, the variations in the sections of the veinulesand arterioles are studied in vivo in the model of the dorsal cutaneouschamber of conscious hamsters, after a video microscopic recording(microscope Leitz Ergolux equipped with a halogen source for theillumination and its black-and-white CD video camera HPR 610) andcomputer analysis (software Visicap, Pack ICAP) of the images.

After anesthesia with sodium pentobarbital (60 mg/kg in i.p.administration), the back of the animal is shaved and hair is pulled soas to be able to put an observation chamber (Professor Gebhard,Heidelberg) on the back skin. The two parts of this chamber are sewnafter careful removal of a certain level of skin thicknesses, which canimpede the observation. A jugular catheter is placed for the i.v.administration of the products, 48 h after the operation.

Effects on the Induced Capillary Hyperpermeability:

The vascular permeability is studied in vivo by measuring theextravasation of albumin, the quantity of which is determined using analbumin-binding dye (Evans blue).

The hyperpermeability is induced by the intradermal injection of asolution of histamine, bradykinin, or zymosan.

The technique is derived from that described by Beach & Steinetz, J.Pharmacol. Exp. Therap., 1961, Vol. 131: pp. 400-406.

The abdominal walls of the rats (Wistar, 200-230 g) are shorn 1 h beforethe start of the experiment. The product to be tested is injected by theintraperitoneal route or orally 1-4 h before the sacrifice. The rats areanesthetized with a halothane mixture. They then receive an intradermalinjection in their abdomen of 0.10 or 0.15 mL (or for histamine 6.7 or10 μm) of inflammatory agent and an intravenous injection of 1 mL of0.5% Evans blue solution in the vein of the penis. These injections arecarried out 30 min before the sacrificing.

30 min after these two injections, the rats are sacrificed by cervicaldislocation.

At the site of the injection of the inflammatory agent, the skin is cutand placed into glass tubes with a ground[-glass] neck containing 3 mLof fuming hydrochloric acid. The digestion of the skin [by HCl] iscarried out by placing it in contact with a water bath at 37° C. for atleast 1 h; 3 mL of 12.8% benzalkonium chloride are then added. Afterallowing the preparation to stand for 30 min, 7 mL of dichloromethaneare added. The tubes are periodically agitated for 1 h. The aqueousphase is eliminated by aspiration, and the organic “dichloromethane”phase is filtered. The optical densities are quantified by absorptionspectrophotometry at a wavelength of 620 nm, against a blank [control]containing only dichloromethane. The averages of the optical densitiesof the different lots of treated or control animals are calculated, thena percentage of variation of the values corresponding to the treated[experimental] animals compared to those of the control animals iscalculated.

The effect of the compounds on the hyperpermeability induced byinflammatory agents, such as histamine and bradykinin, is also studiedafter intravenous injection in a bolus in the model of the dorsalcutaneous chamber of hamsters and according to the method developed byGimeno et al., described earlier (“A new technique using intravitalvideomicroscopy for macromolecular permeability measurement,” 18^(th)European Congress on Microcirculation, Rome, 1994) using videomicroscopyand image analysis by quantification of the distribution of the intra-and extravascular fluorescence of the fluorescent marker (FITC-Dextran)injected in a bolus through the jugular catheter (63 mg/kg for a volumedefined at 1 mL/kg). The microscope is equipped with a fluorescencesource and a combination of filters (excitation in the blue range450-490 nm, and 515-nm stop filter).

Effects on the Capillary Resistance:

The increase in the capillary resistance is evaluated by themodification of the petechial index (negative pressure inducing theextravasation of the erythrocytes), measured by a method derived fromthe angiosterrometer of Parrot.

The studies are carried out on male Wistar rats with an average weightof 200 g (approximate age six weeks). The bottom area of the back isshorn, then the hair is pulled by means of a paste based on a derivativeof thioglycolic acid and calcium hydroxide. After approximately 30 min,the skin is abundantly rinsed and dried.

On the day of the study, the rats are maintained without constraint. Alow pressure of 80 mm of mercury is applied. If the petechiae(extravasation of erythrocytes) have not appeared within 15 sec, the lowpressure is increased as a countermeasure, keeping the suction cap atthe same place.

The minimum low pressure where petechias appear, in mm of mercury,expresses the basal capillary resistance (before any treatment). Twomeasurements are made for each test at different sites on of the back.

The rats are treated by the oral route. After a predetermined time(generally 2, 4, 6 h) following the treatment, the test is repeated ondifferent areas of the skin, until petechias appear, thus leading to anew low pressure index. All the measurements are done in the blind mode.

A percentage of variation in the capillary resistances of the animalstreated compared to their basal capillary resistance is calculated foreach compound studied, at each treatment time and compared with thecontrol group (excipient only) or the reference group.

Effects on Induced Pleurisy in Rats:

The anti-inflammatory activity of the compounds is also studied bymeasuring the inhibition of the edema and the leukocyte migration afterthe induction of pleurisy in rats by the injection of carrageenin intothe pleural cavity (Almeida et al., J. Pharmacol. Exp. Therap., 1980,Vol. 214: p. 74). The rats are treated orally using the compounds 2 hbefore the injection of carrageenin, and 2 and 4 h after this injection.After a predetermined time (6 h) following the induction of pleurisy,the rats are sacrificed; the pleural liquid is recovered by aspiration,and its volume is measured. The leukocytic cells are counted using the“cell counter” technique. The results are expressed as the number ofleukocytes in the exudate expressed with respect to 100 g of animalweight and compared with those of the control lot.

Effect Against Septic Shock:

The activity in septic shock is studied in rats after the induction ofthe shock by an intravenous injection in the bolus of alipopolysaccharide endotoxin (LPS: 15 mg/kg) of E. col, in a methodsimilar to that described by Terashita et al., Eur. J. Pharmacol., 1985,Vol. 109: pp. 257-261. The arterial pressures are measured as a functionof time and comparatively between treated groups and control groups(excipient alone). The compounds are administered intravenously ororally, 5 min or 2 h, respectively, before the injection of LPS.

Examples of Pharmacological Effects:

The compounds of the invention and their possible salts selectivelyincrease, in a majority of the cases, the contraction of the animalveins produced by noradrenaline, by electrical stimulation, or by adepolarizing hyperpotassic solution.

The contractile effect of different compounds on the saphenous vein inrabbits, precontracted by a depolarizing “physiological” solution with apotassium concentration of 40 mM, is given as an illustration; themaximum effect produced by each compound is expressed as a percentage ofthe maximum contraction induced by depolarizing hyperpotassic solutionsand as value of ED₅₀):

Compounds

Emax (% maximum contraction)

ED₅₀ (nM)

Example f

15±1

21

Example j

16±6

30

Example k

26±9

70

Example h

29±6

86

Example i

18±1

90

Example n

24±3

110

Example 3

17±6

36

Example 4

29±11

42

Example 7

17±2

36

Example 13

21±3

57

Example 18

39±6

88

Example 19

20±8

75

Example 20

24±4

110

Example 28

29±2

37

Example 38

12±1

160

Example 59

18±4

53

Example 57

22±3

41

For the purpose of illustration, the oral administration of certaincompounds of the invention and of their possible salts increases thecapillary resistance of rats at doses generally between 0.01 and 5mg/kg:

Compounds

Effects after 4 h

Effect after 6 h

(as a % of the control)

(as a % of the control)

Example 3

5 mg/kg

27

18

Example 18

5 mg/kg

25

28

Example 21

5 mg/kg

10

22

Example f

0.1 mg/kg

7

17

Example h

0.1 mg/kg

19

19

Example 1

0.1 mg/kg

37

35

Example n*

0.1 mg/kg

45

45

Example 2

0.1 mg/kg

25

28

Example 10

0.1 mg/kg

25

46

Example 15

0.1 mg/kg

20

27

Example 28**

0.1 mg/kg

10

13

(granulometry: 0.5-0.6 mm)

(granulometry: 0.6-0.7 mm)

For purposes of illustration, the oral administration of certaincompounds of the invention and of their possible salts reduces theinflammatory hyperpermeability induced by zymosan in rats at doses of0.1-5 mg/kg:

Compounds

Effect after 2 h

Effect after 4 h

(as a % of the control)

(as a % of the control)

Example 1

5 mg/kg

−28

−28

Example n

5 mg/kg

0

−21

Example 21

5 mg/kg

−22

−21

Example 28

5 mg/kg

−29

0

Example f

0.1 mg/kg

−15

−22

Example j

0.1 mg/kg

−14

−32

Example 3

0.1 mg/kg

−22

−26

Example 14

0.1 mg/kg

−31

−15

Example 17

0.1 mg/kg

−15

−23

Example 25

0.1 mg/kg

−14

−17

Example 26

0.1 mg/kg

−14

−24

Example 38

0.1 mg/kg

−12

−3

Example 59

0.1 mg/kg

−13

+21

Moreover, the compounds of the invention and their possible salts have avery low toxicity. For example, after the single oral administration of500 mg/kg in mice, no observable toxic effect and no mortality wasobserved with a majority of the compounds, particularly for Example f (1g/kg), Example j, Example h (1 g/kg; diarrheas), Example n (1 g/kg; redurine), Example 3 (slight diarrheas), Example 5, Example 6, and Example13 (1 g/kg). Most of the compounds were shown to be noncytotoxic (withthe viability of the cells being measured by quantification of thecellular incorporation of neutral red) up to concentrations equal totheir solubility in an aqueous medium on fibroblastic cell lines of mice(L929), particularly Example f, Example j, Example 3, Example 4, Example20, Example 21 . . . .

Of the active compounds of the invention, particular mention is made ofExample n.

Example n, for example, selectively potentiates the contractile responseof the saphenous vein in rabbits due to noradrenaline (value of ED₅₀reduced by a factor of ten and Emax increased by 30%), due to electricalstimulation (increase of 200% at 0.3 μm), and due to serotonin, inaddition to the contractile effects observed in the presence of aresponse to a hyperpotassic solution. Under these depolarizinghyperpotassic conditions, the product contracts, for example, thejugular vein of rabbits (ED₅₀=16 nM), the rat (ED₅₀=50 nM), the perfusedmesenteric venous network of rats (ED₅₀=300 nM), the carotid arteries ofrats (ED₅₀=300 nM), rabbits (ED₅₀=120 nM), and the basilar artery ofrabbits. In the model of the dorsal cutaneous chamber in hamsters,Example n (28 mg/kg injected in an i.v. bolus) reduces the veinulediameter but not the arteriolar diameter after the i.v. injection ofhistamine (1 mg/kg) and it reduces the vascular hyperpermeabilityintroduced by the latter. The oral effect of Example n on the capillaryresistance of the rat is dose dependent over a broad range of doses andits duration of action, of at least 6 h, correlates with its measuredplasma concentrations.

After 2 h, the oral administration of 0.1 mg/kg of product of Example ndecreases the hyperpermeability induced by histamine by 26% compared tothe control group in rats.

The oral administration of 3×5 mg of this product significantlydecreases the volume of pulmonary exudate after the induction ofpleurisy by carrageenin in rats.

When administered in an i.v. bolus at a dose of 28 mg/kg 5 min beforethe induction of septic shock, the product of Example n increases theaverage arterial pressure by 20 mm of mercury compared to the controlrat group.

The product of Example n does not affect the arterial pressure of theanesthetized rat after the i.v. injection in a bolus at least up to 28mg/kg, nor that of the couscious rat after the oral administration of0.1-5-50 mg/kg.

The preceding shows that the compounds of the invention and theirpossible salts can be used in human and animal therapy. They areparticularly indicated for organic functional venous insufficiency andthe hemorrhoid pathologies due to their vascular and anti-inflammatorycomponents, as well as for typical inflammatory disorders and in thecase of shock consisting of a large drop in arterial pressure. In thelatter case, an improvement of the venous return is capable ofmaintaining the cardiac output, and hence the arterial pressure.

The functional venous insufficiency is characterized by a dilation and ahyperdistensibility of the superficial veins of the lower limbs, edemas,and impatience paresthesia of the restless leg type. This type ofpathology may evolve toward organic venous insufficiency characterizedby the development of varicose veins, valvular incontinence, and evenphlebothrombosis and trophic disorders leading to ulcerous lesions.

In this venous pathology, an inflammatory component develops in thefirst stages and manifests itself more clearly in the advanced stages.

Due to their vasoconstrictive, anti-inflammatory effects particularly onthe vascular hyperpermeability and their contractile effects on thecerebral arteries, the compounds of the invention and their possiblesalts are also indicated in migraine.

The present invention thus comprises the use of the compounds mentionedabove and of their possible salts, as active ingredients in thepreparation of drugs and of pharmaceutical compounds for human andveterinary use, comprising at least one of said compounds and salts inassociation with a physiologically acceptable support or diluent. Theform of these drugs and pharmaceutical compositions will naturallydepend on the desired route of administration, which notably may beoral, parenteral, topical (cutaneous), and rectal, and they can beformulated according to the standard techniques with the use of theusual supports and vehicles.

Thus, in the case of oral administration, they can be in the form ofpills, tablets, gels, solutions, syrups, emulsions, suspensions,powders, granules, soft capsules, lyophilizates, microcapsules, andmicrogranules.

The pills, tablets, and gels contain the active ingredient together witha diluent (for example, lactose, dextrose, sucrose, mannitol, maltitol,xylitol, sorbitol, or cellulose), a lubricant (for example, silica,talc, or stearate), a binder (for example, starch, methylcellulose, orgum arabic), a disintegration agent (alginate, for example), and theyare manufactured by known techniques, for example, mixing, granulation,pellet formation, coating, compression, etc.

The syrups can contain, as a support, glycerol, mannitol, and/orsorbitol. The solutions and suspensions can comprise water and otherphysiologically compatible solvents and a support such as a natural gum,agar-agar, sodium alginate, or polyvinyl alcohol.

For parenteral administration, the drugs and compositions can be in theform of solutions, emulsions, or suspensions comprising the activeingredient and an appropriate support or solvent such as sterile wateror sterile isotonic saline solutions.

For the cutaneous application, the drugs and compositions can be in theform of an ointment, cream or gel, or in the form of an emulsion orsuspension, solution, mousse, or powder.

For rectal application, the drugs and compositions can be in the form ofa capsule, cream, emulsion, gel, mousse, ointment, or suppository.

What is claimed is:
 1. A method for the treatment of illness associatedwith an alteration in venous function and/or inflammatory edems whichcomprises administering a sufficient amount of a tricyclic derivative ora pharmaceutically-acceptable salt thereof having the general formula:

in which: A is either a sulfur or an oxygen atom or an R₃N radical whereR₃ is a hydrogen atom, a C₁-C₅ alkyl radical, a substituted orunsubstituted aromatic ring, or a substituted or unsubstitutedheteroaromatic ring; R₁ is either a C₁-C₅ alkyl radical, or an R_(a)NHradical where R₄ is a hydrogen atom, a C₁-C₅ alkyl radical, asubstituted or unsubstituted aromatic ring, or a substituted orunsubstituted heteroaromatic ring, an aromatic ring that may or may notbe substituted by one or more acceptor or donor groups, or aheteroaromatic ring having one or more heteroatoms, which may or may notbe substituted by acceptor or donor groups; R₂ is a hydrogen atom,halogen atom, a C₁-C₅ alkyl radical, an oxygen atom that may or may notbe substituted by a C₁-C₅ alkyl radical, or an NR₅R_(5′) radical whereR₅ and R_(R′) are, independently of each other, a hydrogen atom, anoxygen atom or monovalent C₁-C₅ organic radical, for treatment ofillness connected with an alteration in venous function and/orinflammatory edema.
 2. The method of claim 1 wherein said treatment isfor the treatment of functional and organic venous insufficiency.
 3. Themethod of claim 1 wherein said treatment is for the treatment ofhemorrhoidal pathologies.
 4. The method of claim 1 wherein saidtreatment is for the treatment of migraines.
 5. The method of claim 1wherein said treatment is for the treatment of dermatological andcardiovascular osteoarticular inflammations.
 6. The method of claim 1wherein said treatment is for the treatment of states of shockconsisting of a large drop in arterial blood pressure.
 7. The method ofclaim 6, wherein said shock is septic shock.
 8. The method of claim 1wherein said tricyclic derivative is4,9-dihydro-4,9-dioxo-2-(2-furyl)-naphtho[2,3-d]thiazole.